RESSALVA Atendendo solicitação do(a) autor(a), o texto completo desta dissertação será disponibilizado somente a partir de 20/12/2023. 1 ________________________________________________________________ ÁCIDOS GRAXOS DERIVADOS DE GELEIA REAL COMO FONTE DE INIBIDORES DE DESACETILASES DE HISTONAS HUMANAS: PERSPECTIVAS PARA A TERAPIA EPIGENÉTICA DO CÂNCER DE MAMA FERNANDA APARECIDA DOS SANTOS FRANCE BOTUCATU – SP 2021 2 UNIVERSIDADE ESTADUAL PAULISTA “JÚLIO DE MESQUITA FILHO” INSTITUTO DE BIOCIÊNCIAS DE BOTUCATU ÁCIDOS GRAXOS DERIVADOS DE GELEIA REAL COMO FONTE DE INIBIDORES DE DESACETILASES DE HISTONAS HUMANAS: PERSPECTIVAS PARA A TERAPIA EPIGENÉTICA DO CÂNCER DE MAMA DISCENTE: FERNANDA APARECIDA DOS SANTOS FRANCE ORIENTADORA: PROFª DRª CLÁUDIA APARECIDA RAINHO Dissertação apresentada ao Instituto de Biociências, Campus de Botucatu, UNESP, como parte dos pré-requisitos necessários para obtenção do título de Mestre junto ao Programa de Pós- Graduação em Ciências Biológicas (Genética). BOTUCATU – SP 2021 3 FICHA CATALOGRÁFICA ELABORADA PELA SEÇÃO TÉC. AQUIS. TRATAMENTO DA INFORM. DIVISÃO TÉCNICA DE BIBLIOTECA E DOCUMENTAÇÃO - CÂMPUS DE BOTUCATU - UNESP BIBLIOTECÁRIA RESPONSÁVEL: ROSEMEIRE APARECIDA VICENTE-CRB 8/5651 France, Fernanda Aparecida dos Santos. Ácidos graxos derivados de geleia real como fonte de inibidores de desacetilases de histonas humanas: perspectivas para a terapia epigenética do câncer de mama / Fernanda Aparecida dos Santos France. - Botucatu, 2021 Dissertação (mestrado) - Universidade Estadual Paulista "Júlio de Mesquita Filho", Instituto de Biociências de Botucatu Orientador: Cláudia Aparecida Rainho Capes: 20200005 1. Mamas - Câncer. 2. Epigenética. 3. Inibidores de histona desacetilases. 4. Geleia real. Palavras-chave: 10-HDA; Câncer de mama triplo negativo; Geleia real; HDAC; Terapia epigenética. 5 Dedicatória ____________________________________________________ Dedico este trabalho aos meus pais: Francisco e Maria. Tenho orgulho de ser filha de vocês, sou grata pelos privilégios, pelo apoio, pelo amor e por sempre ajudarem na realização dos meus (e nossos) sonhos. Negra, da periferia, filha de técnica em enfermagem e pedreiro, sou a primeira da família a obter ensino superior completo e mestrado. E é graças a vocês. 6 Agradecimentos ________________________________________________________ Agradeço aos meus pais, pelo apoio incondicional. Amo vocês. Agradeço à minha orientadora Profª. Drª. Cláudia Aparecida Rainho, pela orientação, pelos ensinamentos, pelo apoio e por todas as oportunidades de crescimento e aprendizado. Agradeço pela confiança e pelo carinho. Agradeço à nossa equipe do Laboratório de Epigenética: João, Diogo, Barbara, Naiade, Francieli e Marcos. Sempre aprendo muito com vocês. Agradeço aos integrantes da banca do prévio Exame Geral de Qualificação pelas contribuições extremamente pertinentes, os professores Rafael Henrique Nóbrega (Departamento de Biologia Estrutural e Funcional, IBB-UNESP), Valéria Cristina Sandrim (Departamento de Biofísica e Farmacologia, IBB-UNESP e Roberto da Silva Gomes (Department of Pharmaceutical Sciences, North Dakota State University, NDSU-USA). Aos integrantes da banca de defesa: Profa. Dra. Adriana Camargo Ferrasi (Departamento de Clínica Médica, FMB-UNESP) e Prof. Dr. Lucas Tadeu Bidinotto (Faculdade de Ciências da Saúde de Barretos Dr. Paulo Prata – FACISB) por terem aceitado o convite para avaliar a versão da dissertação e comporem a banca. Agradeço aos meus amigos, que estiveram sempre acreditando em mim. Vocês são pessoas incríveis, amo vocês. Por fim, agradeço à Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil - CAPES pela bolsa de mestrado concedida, processo nº 88882.432974/2019-01 e pelo auxílio para a capacitação no exterior com financiamento de bolsa de estudos, no âmbito do Programa Capes-PrInt, processo nº 88887.310463/2018-00, mobilidade nº 88887.570051/2020-00. 7 Epígrafe ________________________________________________________ “Life is not easy for any of us. But what of that? We must have perseverance and above all confidence in ourselves. We must believe that we are gifted for something and that this thing must be attained”. – Marie Curie “A vida não é fácil para qualquer um de nós. Mas e aí? Devemos perseverar e acima de tudo, confiar em nós mesmos. Devemos crer que temos talento para alguma coisa e buscar alcançá-la”. Tradução livre e recorte de: https://www.mariecurie.org.uk/who/our-history/marie-curie-the-scientist 8 Resumo O câncer consiste em um conjunto de doenças heterogêneas, responsáveis for notória mortalidade e morbidade no mundo, sendo a segunda maior causa de morte antes dos 70 anos de idade no Brasil. Particularmente, o câncer de mama é o segundo tipo mais incidente e o mais prevalente entre as mulheres (excluindo-se o câncer de pele do tipo não melanoma). O câncer de mama é uma doença complexa que envolve diversas alterações genéticas e epigenéticas. A desregulação epigenética tem um papel essencial no desenvolvimento e progressão tumoral, bem como na aquisição de resistência à quimioterapia. A terapia epigenética é uma ferramenta promissora para o tratamento ou sensibilização de tumores aos protocolos clássicos, melhorando sua eficiência. Dentre as diferentes estratégias para a terapia epigenética, as desacetilases de histonas (HDACs) são os alvos mais estudados em ensaios clínicos, geralmente em combinação com radioterapia ou quimioterapia citotóxica/genotóxica, imunoterapia, hormonioterapia ou direcionadas a alvos específicos. Dados prévios do nosso grupo de pesquisa indicam o potencial de que o ácido 10-hidróxi-2-decenóico (10-HDA), derivado da geleia real, seja um possível inibidor de desacetilases de histonas (HDACi). Neste contexto, o presente estudo foi delineado com o objetivo de identificar novos HDACi dentre os ácidos graxos derivados da geleia realO estudo será apresentado em duas partes (capítulos). O primeiro capítulo apresenta as bases teóricas da terapia epigenética, seu potencial uso no câncer de mana e a evidências sobre o 10-HDA como um potencial HDACi. O segundo capítulo corresponde à versão premilinar do manuscrito contendo: a análise de expressão diferencial determinada por RNA-Seq dos genes codificadores de HDACs recuperados do projeto The Cancer Genome Atlas (TCGA Research Network: https://www.cancer.gov/tcga); a descrição dos ácidos graxos derivados da geleia real quanto suas características estruturais, físico-químicas e principais componentes compartilhados entre as moléculas (chamados de cores); in silico screening com os ácidos graxos derivados da geleia real por meio do método docking molecular para determinar as possíveis interações com a proteína humana modelo HDAC2, comparada com o inibidor conhecido, ácido hidroxâmico suberoilanilida (SAHA). Globalmente, os resultados indicam que os ácidos graxos da derivados da geleia real podem ocupar o domínio catalítico da HDACs de modo semelhante ao inibidor conhecido (SAHA) e indicam as melhores moléculas candidatas para os estudos futuros baseados em ensaios bioquímicos de inibição de HDACs, bem como ensaios funcionais in vitro para investigar o potencial efeito de ácidos graxos na sensibilização de linhagens celulares resistentes à quimioterápicos comumente utilizados na prática oncológica. Palavras-chave: 10-HDA; Câncer de mama triplo negativo; Geleia real; HDAC; Terapia epigenética. 9 Abstract Cancer consists of a heterogenous group of diseases, responsible for notorious mortality and morbidity worldwide, considered the second main cause of death before 70 years old in Brazil. Particularly, breast cancer is one of the most incidents and more prevalent among women (excluding non-melanoma skin cancer). Breast cancer is a complex disease that involves several genetic and epigenetic alterations. The epigenetic dysregulation has an essential role in tumor development and progression, as well as chemotherapy resistance acquisition, therefore epigenetic therapy of cancer is promising tool for treatment or sensitization of tumors to the classical therapeutic protocols, increasing efficacy of response. In the different possible strategies for epigenetic therapy of cancer, the histone deacetylases (HDACs) are the most studied targets in clinical trials, usually combined with radiotherapy or cytotoxic/genotoxic chemotherapy, immunotherapy, hormonal therapy or targeted therapies. Previous data of our research group indicates the potential of the 10-hydroxy-2-decenoic acid (10-HDA), derived from royal jelly, as a possible new HDAC inhibitor (HDACi). This present work is composed of two parts (chapters). The first is an introduction to the theorical basis of epigenetic therapy of breast cancer and its possible use in breast cancer, the current evidence regarding 10-HDA as a potential HDACi. The second chapter is the preliminary version of the manuscript that is yet to be finished and submitted, with our preliminary data: differential expression analysis (RNAseq data) of HDAC coding genes in human cancers from The Cancer Genome Atlas (TCGA Research Network: https://www.cancer.gov/tcga); structural and physicochemical description of royal jelly derived fatty acids and their core structures; in silico screening with the fatty acids using the molecular docking method to determinate the possible interactions with human HDAC2 model, with a well-stablished inhibitor, suberoylanilide hydroxamic acid (SAHA). Overall, the results show that the royal jelly derived fatty acids might occupy the catalytic domain of HDACs, similarly to the known inhibitor (SAHA) and suggest candidate molecules for future assays based on biochemical inhibition of HDACs, as well as functional assay in vitro in order to investigate the potential effects of royal jelly derived fatty acids in sensitization of breast cancer cell lines resistant to chemotherapeutical agents routinely used in oncological practice. Keywords: 10-HDA; triple negative breast câncer; royal jelly; HDAC; epigenetic therapy. 14 Summary ________________________________________________________ Chapter I: an overview about cancer and the emerging role of epigenetic therapy in breast cancer treatment ..................................................................................................................... 15 1. Background ..................................................................................................................... 15 1.1.Epidemiology .............................................................................................................. 15 1.2. Breast Cancer ............................................................................................................. 17 1.3. Triple Negative Breast Cancer .................................................................................. 21 1.4. Epigenetic therapy: histone deacetylase inhibitors as promising modulators for chemosensitization .................................................................................................... 23 1.5. In silico approaches for identification of small molecule for epigenetic therapy (epi- informatics) .......................................................................................................... 32 2.1. General Objetive ......................................................................................................... 35 2.2. Specific Objectives ......................................................................................... 35 3. Conclusions ........................................................................................................ 36 3. References............................................................................................................................ 27 Chapter II: Research article (in preparation) ..................................................................... 51 Abstract ......................................................................................................................... 51 1. Introduction ................................................................................................................ 52 2. Materials and Methods ............................................................................................... 54 2.1. Expression profile of classical histone deacetylases in human cancer ..................... 54 2.2. The histone deacetylase family in Apis mellifera and Homo sapiens genomes ........ 55 2.3. Royal jelly derived fatty acids: characterization of physicochemical and structural properties ........................................................................................................................... 56 2.4. Molecular Docking .................................................................................................... 57 3. Results ............................................................................................................................... 58 3.1. Histone deacetylases are differentially expressed among human cancers ................. 58 3.2. The histone deacetylase domains are conserved in Apis mellifera and Homo sapiens ........................................................................................................................................... 60 3.3. Chemical diversity of royal jelly derived fatty acids ................................................. 64 3.4. Royal jelly derived fatty acids might interact with HDAC2 domain ......................... 68 4. Discussion .......................................................................................................................... 72 5. Conclusions ....................................................................................................................... 76 6. References ......................................................................................................................... 77 37 3. Conclusions By using in silico approaches, the present study contributed to the scientific literature with new insights in drug development and discovery from products of natural origin. Overall, the findings suggest that fatty acids derived from royal jelly can inhibit human HDACs. Among the differentially expressed genes encoding HDACs, there is a trend of the ubiquitous HDACs (class I) to be up-regulated in most cancers. HDAC2 gene is one of most frequently overexpressed in human cancer, including breast cancer. Fatty acids derived from royal jelly are very similar to the 10-HDA, its major and unique fatty acid, which suggests that they may have similar biological functions in royal jelly, notably considering the analysis of core structures that indicated three key clusters: 3-hydroxydecanoic acid and Methyl 3-hydroxydecanoate in the first; Trans-10-acetoxydec-2-enoic acid and 10- hydroxy-2-decenoic acid in the second; and Octanoic acid and 2-decene-1,10-dioic acid in the third cluster. . Using this information, it was demonstrated that these fatty acids might interact with the catalytic domain of human HDAC2, similar to suberoylanilide hydroxamic acid (SAHA), a well-known HDACi. The aforementioned data strengths the hypothesis of an additive effect of these fatty acids in royal jelly. These findings support the design of future experimental approaches devoted to validating the inhibitory activity of fatty acids on HDACs and the potential use of this chemical compounds in pre-clinical studies for the identification of new drugs for epigenetic therapy. 38 4. References: 1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209–49. 2. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin [Internet]. 2018 Nov 1 [cited 2020 Feb 29];68(6):394–424. Available from: http://doi.wiley.com/10.3322/caac.21492 3. Omran AR. The epidemiologic transition. A theory of the epidemiology of population change. Milbank Mem Fund Q. 1971 Oct;49(4):509–38. 4. Gersten O, Wilmoth JR. The Cancer Transition in Japan since 1951. Demogr Res [Internet]. 2002 Nov 25;7:271–306. Available from: http://www.jstor.org/stable/26348061 5. Bray F, Jemal A, Grey N, Ferlay J, Forman D. Global cancer transitions according to the Human Development Index (2008–2030): a population-based study. Lancet Oncol [Internet]. 2012 Aug 1;13(8):790–801. Available from: https://doi.org/10.1016/S1470- 2045(12)70211-5 6. Kocarnik J. Cancer’s global epidemiological transition and growth. Lancet [Internet]. 2020 Mar 7;395(10226):757–8. Available from: https://doi.org/10.1016/S0140- 6736(19)32046-X 7. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin [Internet]. 2018 Nov [cited 2019 Aug 31];68(6):394–424. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30207593 8. INCA. Estimativa 2020: incidência de câncer no Brasil [Internet]. Rio de Janeiro; 2019. Available from: https://www.inca.gov.br/sites/ufu.sti.inca.local/files//media/document//estimativa- 2020-incidencia-de-cancer-no-brasil.pdf 9. ORGANIZATION WH. WORLD HEALTH STATISTICS 2019: monitoring health for the sdgs, sustainable development goals. Geneva: WORLD HEALTH ORGANIZATION; 2019. 10. Du T, Zhu L, Levine KM, Tasdemir N, Lee A V, Vignali DAA, et al. Invasive lobular and ductal breast carcinoma differ in immune response, protein translation efficiency and metabolism. Sci Rep [Internet]. 2018;8(1):7205. Available from: 39 https://doi.org/10.1038/s41598-018-25357-0 11. McCart Reed AE, Kalita-De Croft P, Kutasovic JR, Saunus JM, Lakhani SR. Recent advances in breast cancer research impacting clinical diagnostic practice. J Pathol. 2019 Apr;247(5):552–62. 12. Hoon Tan P, Ellis I, Allison K, Brogi E, Fox SB, Lakhani S, et al. The 2019 WHO classification of tumours of the breast. Histopathology. 2020 Feb; 13. Turashvili G, Brogi E. Tumor Heterogeneity in Breast Cancer. Front Med [Internet]. 2017 Dec 8;4. Available from: http://journal.frontiersin.org/article/10.3389/fmed.2017.00227/full 14. Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow- up. Histopathology. 1991 Nov;19(5):403–10. 15. Sobin LH, Fleming ID. TNM classification of malignant tumors, fifth edition (1997). Cancer [Internet]. 1997 Nov 1;80(9):1803–4. Available from: http://doi.wiley.com/10.1002/%28SICI%291097- 0142%2819971101%2980%3A9%3C1803%3A%3AAID-CNCR16%3E3.0.CO%3B2- 9 16. Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, et al. AJCC Cancer Staging Manual [Internet]. 8th ed. Amin MB, Edge SB, Greene FL, Byrd DR, Brookland RK, Washington MK, et al., editors. Cham: Springer International Publishing; 2017. 24–26 p. Available from: http://link.springer.com/10.1007/978-3-319-40618-3 17. Parker JS, Mullins M, Cheang MCU, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol [Internet]. 2009/02/09. 2009 Mar 10;27(8):1160–7. Available from: https://pubmed.ncbi.nlm.nih.gov/19204204 18. Perou CM, Sørlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, et al. Molecular portraits of human breast tumours. Nature [Internet]. 2000 Aug 17 [cited 2019 Aug 31];406(6797):747–52. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10963602 19. Prat A, Perou CM. Deconstructing the molecular portraits of breast cancer. Vol. 5, Molecular Oncology. John Wiley and Sons Ltd; 2011. p. 5–23. 20. Tsang JYS, Tse GM. Molecular Classification of Breast Cancer. Adv Anat Pathol. 2020 Jan;27(1):27–35. 21. Bernhardt SM, Dasari P, Walsh D, Townsend AR, Price TJ, Ingman W V. Hormonal Modulation of Breast Cancer Gene Expression: Implications for Intrinsic Subtyping in 40 Premenopausal Women [Internet]. Vol. 6, Frontiers in Oncology . 2016. p. 241. Available from: https://www.frontiersin.org/article/10.3389/fonc.2016.00241 22. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nat Rev Dis Prim [Internet]. 2019 Dec 23;5(1):66. Available from: http://www.nature.com/articles/s41572-019-0111-2 23. INCA. A situação do câncer de mama no Brasil: síntese de dados dos sistemas de informação [Internet]. (INCA) IN de CJAG da S, editor. Rio de Janeiro; 2019. 1–89 p. Available from: https://www.inca.gov.br/sites/ufu.sti.inca.local/files//media/document//a_situacao_ca_ mama_brasil_2019.pdf 24. Nedeljković M, Damjanović A. Mechanisms of Chemotherapy Resistance in Triple- Negative Breast Cancer—How We Can Rise to the Challenge. Cells [Internet]. 2019 Aug 22 [cited 2019 Oct 3];8(9):957. Available from: http://www.ncbi.nlm.nih.gov/pubmed/31443516 25. Carey LA, Dees EC, Sawyer L, Gatti L, Moore DT, Collichio F, et al. The Triple Negative Paradox: Primary Tumor Chemosensitivity of Breast Cancer Subtypes. Clin Cancer Res [Internet]. 2007 Apr 15;13(8):2329–34. Available from: http://clincancerres.aacrjournals.org/cgi/doi/10.1158/1078-0432.CCR-06-1109 26. Bianchini G, Balko JM, Mayer IA, Sanders ME, Gianni L. Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease. Nat Rev Clin Oncol [Internet]. 2016;13(11):674–90. Available from: http://dx.doi.org/10.1038/nrclinonc.2016.66 27. Ministério da Saúde (BR). PORTARIA CONJUNTA No 19, DE 3 DE JULHO DE 2018. Aprova as Diretrizes Diagnósticas e Terapêuticas do Carcinoma de Mama [Internet]. Página 59 da Seção 1 do Diário Oficial da União (DOU) de 16 de Julho de 2018. 2018. Available from: http://conitec.gov.br/images/Protocolos/DDT/DDT-Carcinoma-de- mama_PORTARIA-CONJUNTA-N--5.pdf 28. Al-Mahmood S, Sapiezynski J, Garbuzenko OB, Minko T. Metastatic and triple-negative breast cancer: challenges and treatment options. Drug Deliv Transl Res [Internet]. 2018 Oct 5;8(5):1483–507. Available from: http://link.springer.com/10.1007/s13346-018- 0551-3 29. Neophytou C, Boutsikos P, Papageorgis P. Molecular mechanisms and emerging therapeutic targets of triple-negative breast cancer metastasis. Front Oncol. 2018;8(FEB). 30. Longley D, Johnston P. Molecular mechanisms of drug resistance. J Pathol [Internet]. 2005 Jan [cited 2019 Oct 2];205(2):275–92. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15641020 41 31. Tomar D, Yadav AS, Kumar D, Bhadauriya G, Kundu GC. Non-coding RNAs as potential therapeutic targets in breast cancer. Biochim Biophys Acta - Gene Regul Mech [Internet]. 2020 Apr;1863(4):194378. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1874939919300161 32. Calanca N, Abildgaard C, Rainho CA, Rogatto SR. The interplay between long noncoding rnas and proteins of the epigenetic machinery in ovarian cancer. Vol. 12, Cancers. MDPI AG; 2020. p. 1–21. 33. McGranahan N, Swanton C. Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. Cell [Internet]. 2017;168(4):613–28. Available from: https://www.sciencedirect.com/science/article/pii/S0092867417300661 34. Bird A. Perceptions of epigenetics. Nature [Internet]. 2007;447(7143):396–8. Available from: https://doi.org/10.1038/nature05913 35. Aristizabal MJ, Anreiter I, Halldorsdottir T, Odgers CL, McDade TW, Goldenberg A, et al. Biological embedding of experience: A primer on epigenetics. Proc Natl Acad Sci [Internet]. 2020 Sep 22;117(38):23261 LP – 23269. Available from: http://www.pnas.org/content/117/38/23261.abstract 36. Audia JE, Campbell RM. Histone Modifications and Cancer. Cold Spring Harb Perspect Biol [Internet]. 2016 Apr 1 [cited 2019 Oct 2];8(4):a019521. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27037415 37. Huang J, Ling K. EZH2 and histone deacetylase inhibitors induce apoptosis in triple negative breast cancer cells by differentially increasing H3 Lys27 acetylation in the BIM gene promoter and enhancers. Oncol Lett [Internet]. 2017 Sep 8 [cited 2019 Oct 2];14(5):5735–42. Available from: http://www.ncbi.nlm.nih.gov/pubmed/29113202 38. Sharma S V., Lee DY, Li B, Quinlan MP, Takahashi F, Maheswaran S, et al. A Chromatin-Mediated Reversible Drug-Tolerant State in Cancer Cell Subpopulations. Cell [Internet]. 2010 Apr 2 [cited 2019 Oct 2];141(1):69–80. Available from: https://www.sciencedirect.com/science/article/pii/S0092867410001807?via%3Dihub#s ec4 39. Mitra D, Das PM, Huynh FC, Jones FE. Jumonji/ARID1 B (JARID1B) Protein Promotes Breast Tumor Cell Cycle Progression through Epigenetic Repression of MicroRNA let- 7e. J Biol Chem [Internet]. 2011 [cited 2019 Oct 2];286(47):40531. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3220509/ 40. Faldoni FL, Rainho CA, Rogatto SR. Epigenetics in Inflammatory Breast Cancer: Biological Features and Therapeutic Perspectives. Vol. 9, Cells . 2020. 41. Li J, Hao D, Wang L, Wang H, Wang Y, Zhao Z, et al. Epigenetic targeting drugs potentiate chemotherapeutic effects in solid tumor therapy. Sci Rep. 2017;7(1):1–13. 42 42. Dawson MA, Kouzarides T. Cancer Epigenetics: From Mechanism to Therapy. Cell [Internet]. 2012 Jul;150(1):12–27. Available from: http://dx.doi.org/10.1016/j.cell.2012.06.013 43. Esteller M. Epigenetics in Cancer. N Engl J Med [Internet]. 2008 Mar 13;358(11):1148– 59. Available from: https://doi.org/10.1056/NEJMra072067 44. Esteller M. Epigenetic gene silencing in cancer: the DNA hypermethylome. Hum Mol Genet [Internet]. 2007 Apr 15;16(R1):R50–9. Available from: https://doi.org/10.1093/hmg/ddm018 45. Hellebrekers D, van Engeland M. Epigenetic Therapy. In: Schwab M, editor. Encyclopedia of Cancer [Internet]. Berlin, Heidelberg: Springer Berlin Heidelberg; 2011. p. 1287–90. Available from: http://link.springer.com/10.1007/978-3-642-16483- 5_1948 46. Morel D, Jeffery D, Aspeslagh S, Almouzni G, Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours — past lessons and future promise. Nat Rev Clin Oncol [Internet]. 2019 Sep 30 [cited 2019 Oct 8];1–17. Available from: http://www.nature.com/articles/s41571-019-0267-4 47. Darwiche N. Epigenetic mechanisms and the hallmarks of cancer: an intimate affair. Am J Cancer Res. 2020;10(7):1954–78. 48. Nebbioso A, Tambaro FP, Dell’Aversana C, Altucci L. Cancer epigenetics: Moving forward. PLoS Genet [Internet]. 2018 Jun 7;14(6):e1007362–e1007362. Available from: https://pubmed.ncbi.nlm.nih.gov/29879107 49. Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science (80- ) [Internet]. 2017 Jul 21 [cited 2019 Aug 2];357(6348):eaal2380. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28729483 50. Medina-Franco JL. Epi-Informatics [Internet]. Boston: Elsevier; 2016. Available from: https://linkinghub.elsevier.com/retrieve/pii/C20140037896 51. Rothbart SB, Baylin SB. Epigenetic Therapy for Epithelioid Sarcoma. Cell [Internet]. 2020;181(2):211. Available from: http://www.sciencedirect.com/science/article/pii/S0092867420303354 52. Mullard A. FDA approves an inhibitor of a novel ‘epigenetic writer.’ Nat Rev Drug Discov [Internet]. 2020 Nov 25;19(3):156. Available from: http://www.nature.com/articles/d41573-020-00024-0 53. Seto E, Yoshida M. Erasers of Histone Acetylation: The Histone Deacetylase Enzymes. Cold Spring Harb Perspect Biol [Internet]. 2014 Feb 24;6(4):a018713–a018713. Available from: 43 http://cshperspectives.cshlp.org/lookup/doi/10.1101/cshperspect.a018713 54. Harada T, Hideshima T, Anderson KC. Histone deacetylase inhibitors in multiple myeloma: from bench to bedside. Int J Hematol [Internet]. 2016;104(3):300–9. Available from: https://doi.org/10.1007/s12185-016-2008-0 55. Ocker M. Deacetylase inhibitors - focus on non-histone targets and effects. World J Biol Chem [Internet]. 2010 Oct 23;1(5):55. Available from: http://www.wjgnet.com/1949- 8454/full/v1/i5/55.htm 56. Glozak MA, Sengupta N, Zhang X, Seto E. Acetylation and deacetylation of non-histone proteins. Gene [Internet]. 2005 Dec 23;363:15–23. Available from: http://linkinghub.elsevier.com/retrieve/pii/S037811190500572X 57. Suraweera A, O’Byrne KJ, Richard DJ. Combination Therapy With Histone Deacetylase Inhibitors (HDACi) for the Treatment of Cancer: Achieving the Full Therapeutic Potential of HDACi. Front Oncol [Internet]. 2018 Mar 29 [cited 2019 Oct 2];8:92. Available from: http://journal.frontiersin.org/article/10.3389/fonc.2018.00092/full 58. Milazzo G, Mercatelli D, Di Muzio G, Triboli L, De Rosa P, Perini G, et al. Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability. Genes (Basel) [Internet]. 2020 May 15;11(5):556. Available from: https://pubmed.ncbi.nlm.nih.gov/32429325 59. Mistry J, Chuguransky S, Williams L, Qureshi M, Salazar GA, Sonnhammer ELL, et al. Pfam: The protein families database in 2021. Nucleic Acids Res. 2021 Jan;49(D1):D412–9. 60. Schuetz A, Min J, Allali-Hassani A, Schapira M, Shuen M, Loppnau P, et al. Human HDAC7 Harbors a Class IIa Histone Deacetylase-specific Zinc Binding Motif and Cryptic Deacetylase Activity. J Biol Chem [Internet]. 2008 Apr 25 [cited 2019 Oct 23];283(17):11355–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18285338 61. Yang XJ, Seto E. The Rpd3/Hda1 family of lysine deacetylases: From bacteria and yeast to mice and men. Vol. 9, Nature Reviews Molecular Cell Biology. Nature Publishing Group; 2008. p. 206–18. 62. Hai Y, Shinsky SA, Porter NJ, Christianson DW. Histone deacetylase 10 structure and molecular function as a polyamine deacetylase. Nat Commun [Internet]. 2017;8(1):15368. Available from: https://doi.org/10.1038/ncomms15368 63. Zou H, Wu Y, Navre M, Sang B-C. Characterization of the two catalytic domains in histone deacetylase 6. Biochem Biophys Res Commun. 2006 Mar;341(1):45–50. 64. Haberland M, Montgomery RL, Olson EN. The many roles of histone deacetylases in 44 development and physiology: implications for disease and therapy. Nat Rev Genet [Internet]. 2009 Jan [cited 2019 Oct 18];10(1):32–42. Available from: http://www.nature.com/articles/nrg2485 65. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone Deacetylase Inhibitors as Anticancer Drugs. Int J Mol Sci [Internet]. 2017 Jul 1;18(7):1414. Available from: https://pubmed.ncbi.nlm.nih.gov/28671573 66. Mohamed MFA, Shaykoon MSA, Abdelrahman MH, Elsadek BEM, Aboraia AS, Abuo- Rahma GE-DAA. Design, synthesis, docking studies and biological evaluation of novel chalcone derivatives as potential histone deacetylase inhibitors. Bioorg Chem [Internet]. 2017 Jun 1 [cited 2019 Oct 9];72:32–41. Available from: https://www.sciencedirect.com/science/article/pii/S0045206816300852?via%3Dihub 67. Zhang L, Zhang J, Jiang Q, Zhang L, Song W. Zinc binding groups for histone deacetylase inhibitors. J Enzyme Inhib Med Chem [Internet]. 2018 Dec;33(1):714–21. Available from: https://pubmed.ncbi.nlm.nih.gov/29616828 68. Prachayasittikul V, Prathipati P, Pratiwi R, Phanus-umporn C, Malik AA, Schaduangrat N, et al. Exploring the epigenetic drug discovery landscape. Expert Opin Drug Discov [Internet]. 2017 Apr 3;12(4):345–62. Available from: http://dx.doi.org/10.1080/17460441.2017.1295954 69. Li Y, Seto E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb Perspect Med [Internet]. 2016 Apr 2;6(10):a026831. Available from: http://perspectivesinmedicine.cshlp.org/lookup/doi/10.1101/cshperspect.a026831 70. Terranova-Barberio M, Thomas S, Ali N, Pawlowska N, Park J, Krings G, et al. HDAC inhibition potentiates immunotherapy in triple negative breast cancer. Oncotarget. 2017 Dec;8(69):114156–72. 71. Miranda Furtado CL, Dos Santos Luciano MC, Silva Santos R Da, Furtado GP, Moraes MO, Pessoa C. Epidrugs: targeting epigenetic marks in cancer treatment. Epigenetics. 2019 Dec;14(12):1164–76. 72. Mazzone R, Zwergel C, Mai A, Valente S. Epi-drugs in combination with immunotherapy: a new avenue to improve anticancer efficacy. Clin Epigenetics. 2017;9:59. 73. Chiappinelli KB, Zahnow CA, Ahuja N, Baylin SB. Combining Epigenetic and Immunotherapy to Combat Cancer. Cancer Res. 2016 Apr;76(7):1683–9. 74. Montalvo-Casimiro M, González-Barrios R, Meraz-Rodriguez MA, Juárez-González VT, Arriaga-Canon C, Herrera LA. Epidrug Repurposing: Discovering New Faces of Old Acquaintances in Cancer Therapy [Internet]. Vol. 10, Frontiers in Oncology . 2020. p. 2461. Available from: 45 https://www.frontiersin.org/article/10.3389/fonc.2020.605386 75. Moufarrij S, Srivastava A, Gomez S, Hadley M, Palmer E, Austin PT, et al. Combining DNMT and HDAC6 inhibitors increases anti-tumor immune signaling and decreases tumor burden in ovarian cancer. Sci Rep [Internet]. 2020;10(1):3470. Available from: https://doi.org/10.1038/s41598-020-60409-4 76. Capobianco E, Mora A, La Sala D, Roberti A, Zaki N, Badidi E, et al. Separate and Combined Effects of DNMT and HDAC Inhibitors in Treating Human Multi-Drug Resistant Osteosarcoma HosDXR150 Cell Line. PLoS One [Internet]. 2014 Apr 22;9(4):e95596. Available from: https://doi.org/10.1371/journal.pone.0095596 77. Li J, Hao D, Wang L, Wang H, Wang Y, Zhao Z, et al. Epigenetic targeting drugs potentiate chemotherapeutic effects in solid tumor therapy. Sci Rep [Internet]. 2017;7(1):4035. Available from: https://doi.org/10.1038/s41598-017-04406-0 78. Lin K-T, Wang Y-W, Chen C-T, Ho C-M, Su W-H, Jou Y-S. HDAC Inhibitors Augmented Cell Migration and Metastasis through Induction of PKCs Leading to Identification of Low Toxicity Modalities for Combination Cancer Therapy. Clin Cancer Res [Internet]. 2012 Sep 1 [cited 2019 Oct 1];18(17):4691–701. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22811583 79. Zhang T, Chen Y, Li J, Yang F, Wu H, Dai F, et al. Antitumor Action of a Novel Histone Deacetylase Inhibitor, YF479, in Breast Cancer. Neoplasia [Internet]. 2014;16(8):665– 77. Available from: http://dx.doi.org/10.1016/j.neo.2014.07.009 80. Marchion DC, Bicaku E, Daud AI, Richon V, Sullivan DM, Munster PN. Sequence- specific potentiation of topoisomerase II inhibitors by the histone deacetylase inhibitor suberoylanilide hydroxamic acid. J Cell Biochem [Internet]. 2004 May 15 [cited 2019 Oct 1];92(2):223–37. Available from: http://doi.wiley.com/10.1002/jcb.20045 81. Munster P, Marchion D, Bicaku E, Lacevic M, Kim J, Centeno B, et al. Clinical and biological effects of valproic acid as a histone deacetylase inhibitor on tumor and surrogate tissues: phase i/ii trial of valproic acid and epirubicin/FEC. Clin Cancer Res. 2009;15(7):2488–96. 82. Marchion DC, Bicaku E, Turner JG, Schmitt ML, Morelli DR, Munster PN. HDAC2 regulates chromatin plasticity and enhances DNA vulnerability. Mol Cancer Ther [Internet]. 2009 Apr 1 [cited 2019 Oct 2];8(4):794–801. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19372552 83. Hii L-W, Chung FF-L, Soo JS-S, Tan BS, Mai C-W, Leong C-O. Histone deacetylase (HDAC) inhibitors and doxorubicin combinations target both breast cancer stem cells and non-stem breast cancer cells simultaneously. Breast Cancer Res Treat. 2020 Feb;179(3):615–29. 46 84. Kiweler N, Wünsch D, Wirth M, Mahendrarajah N, Schneider G, Stauber RH, et al. Histone deacetylase inhibitors dysregulate DNA repair proteins and antagonize metastasis-associated processes. J Cancer Res Clin Oncol [Internet]. 2020/01/13. 2020 Feb;146(2):343–56. Available from: https://pubmed.ncbi.nlm.nih.gov/31932908 85. Münster P, Marchion D, Bicaku E, Schmitt M, Ji HL, DeConti R, et al. Phase I trial of histone deacetylase inhibition by valproic acid followed by the topoisomerase II inhibitor epirubicin in advanced solid tumors: A clinical and translational study. J Clin Oncol. 2007;25(15):1979–85. 86. Munster PN, Marchion D, Thomas S, Egorin M, Minton S, Springett G, et al. Phase I trial of vorinostat and doxorubicin in solid tumours: Histone deacetylase 2 expression as a predictive marker. Br J Cancer [Internet]. 2009;101(7):1044–50. Available from: http://dx.doi.org/10.1038/sj.bjc.6605293 87. Yeruva SLH, Zhao F, Miller KD, Tevaarwerk AJ, Wagner LI, Gray RJ, et al. E2112: randomized phase iii trial of endocrine therapy plus entinostat/placebo in patients with hormone receptor-positive advanced breast cancer. NPJ breast cancer. 2018;4:1. 88. Yardley DA, Ismail-Khan RR, Melichar B, Lichinitser M, Munster PN, Klein PM, et al. Randomized phase II, double-blind, placebo-controlled study of exemestane with or without entinostat in postmenopausal women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on treatment with a nonsteroidal aromat. J Clin Oncol Off J Am Soc Clin Oncol. 2013 Jun;31(17):2128–35. 89. Peterson LM, Kurland BF, Yan F, Novakova-Jiresova A, Gadi VK, Specht JM, et al. (18)F-Fluoroestradiol ((18)F-FES)-PET imaging in a Phase II trial of vorinostat to restore endocrine sensitivity in ER+/HER2- metastatic breast cancer. J Nucl Med. 2020 Jun; 90. Munster PN, Thurn KT, Thomas S, Raha P, Lacevic M, Miller A, et al. A phase II study of the histone deacetylase inhibitor vorinostat combined with tamoxifen for the treatment of patients with hormone therapy-resistant breast cancer. Br J Cancer. 2011 Jun 7;104(12):1828–35. 91. Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2019;4:62. 92. Bates SE. Epigenetic Therapies for Cancer. N Engl J Med [Internet]. 2020 Aug 12;383(7):650–63. Available from: https://doi.org/10.1056/NEJMra1805035 93. Blaney J. A very short history of structure-based design: how did we get here and where do we need to go? J Comput Aided Mol Des. 2012 Jan;26(1):13–4. 94. Jin L, Wang W, Fang G. Targeting protein-protein interaction by small molecules. Annu 47 Rev Pharmacol Toxicol. 2014;54:435–56. 95. Meng X-Y, Zhang H-X, Mezei M, Cui M. Molecular docking: a powerful approach for structure-based drug discovery. Curr Comput Aided Drug Des. 2011 Jun;7(2):146–57. 96. Epi-informatics: discovery and development of small molecule epigenetic drugs and probes. Amsterdam: Elsevier/AP; 2016. 424 p. 97. Salvito D, Fernandez M, Jenner K, Lyon DY, de Knecht J, Mayer P, et al. Improving the Environmental Risk Assessment of Substances of Unknown or Variable Composition, Complex Reaction Products, or Biological Materials. Environ Toxicol Chem [Internet]. 2020 Nov 1;39(11):2097–108. Available from: https://doi.org/10.1002/etc.4846 98. Assumpção JHM, Takeda AAS, Sforcin JM, Rainho CA. Effects of Propolis and Phenolic Acids on Triple-Negative Breast Cancer Cell Lines: Potential Involvement of Epigenetic Mechanisms. Molecules. 2020 Mar;25(6). 99. France F, Assumpção JHM, Rainho CA. Evaluation of antitumor activity of royal jelly and its compound 10-HDA in human breast cancer cell lines: perspectives for epigenetic therapy. In: Second AACR International Conference on Translatinal Cancer Medicine. São Paulo: AACR; 2018. 100. France, F. A. dos S.; Assumpção, J. H. M.; Rainho CA. In Silico Screening Of Bioactive Fatty Acids From Royal Jelly As Potential Histone Deacetylase Inhibitors (HDACi). In: XIX Workshop de Genética. France2019; 2019. p. 38. 101. Chittka A, Chittka L. Epigenetics of Royalty. PLoS Biol [Internet]. 2010 Feb 24;8(11):e1000532. Available from: http://dx.plos.org/10.1371/journal.pbio.1000532 102. Spannhoff A, Kim YK, Raynal NJ-M, Gharibyan V, Su M-B, Zhou Y-Y, et al. Histone deacetylase inhibitor activity in royal jelly might facilitate caste switching in bees. EMBO Rep [Internet]. 2011 Mar 3;12(3):238–43. Available from: http://embor.embopress.org/cgi/doi/10.1038/embor.2011.9 103. Polsinelli GA, Yu HD. Regulation of histone deacetylase 3 by metal cations and 10- hydroxy-2E-decenoic acid: Possible epigenetic mechanisms of queen-worker bee differentiation. PLoS One. 2018;13(12):1–12. 104. Prachayasittikul V, Prathipati P, Pratiwi R, Phanus-Umporn C, Malik AA, Schaduangrat N, et al. Exploring the epigenetic drug discovery landscape. Expert Opin Drug Discov. 2017 Apr;12(4):345–62. 105. Salvador LA, Luesch H. Discovery and mechanism of natural products as modulators of histone acetylation. Curr Drug Targets [Internet]. 2012 Jul;13(8):1029–47. Available from: https://pubmed.ncbi.nlm.nih.gov/22594471 48 106. Salvador LA, Luesch H. Discovery and mechanism of natural products as modulators of histone acetylation. Curr Drug Targets [Internet]. 2012 Jul [cited 2019 Oct 30];13(8):1029–47. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22594471 107. Carlos-Reyes Á, López-González JS, Meneses-Flores M, Gallardo-Rincón D, Ruíz- García E, Marchat LA, et al. Dietary Compounds as Epigenetic Modulating Agents in Cancer. Front Genet [Internet]. 2019 Mar 1 [cited 2019 Mar 26];10. Available from: https://www.frontiersin.org/article/10.3389/fgene.2019.00079/full 108. Ratovitski E. Anticancer Natural Compounds as Epigenetic Modulators of Gene Expression. Vol. 18, Current Genomics. 2017. 175–205 p. 109. Jasek K, Kubatka P, Samec M, Liskova A, Smejkal K, Vybohova D, et al. DNA Methylation Status in Cancer Disease: Modulations by Plant-Derived Natural Compounds and Dietary Interventions. Biomolecules [Internet]. 2019 Jul 18 [cited 2020 Sep 8];9(7):289. Available from: https://www.mdpi.com/2218-273X/9/7/289 110. Shankar E, Kanwal R, Candamo M, Gupta S. Dietary phytochemicals as epigenetic modifiers in cancer: Promise and challenges. Semin Cancer Biol [Internet]. 2016/04/23. 2016 Oct;40–41:82–99. Available from: https://pubmed.ncbi.nlm.nih.gov/27117759 111. Meeran SM, Ahmed A, Tollefsbol TO. Epigenetic targets of bioactive dietary components for cancer prevention and therapy. Clin Epigenetics [Internet]. 2010 Dec 1;1(3–4):101–16. Available from: https://pubmed.ncbi.nlm.nih.gov/21258631 112. Shukla S, Meeran SM, Katiyar SK. Epigenetic regulation by selected dietary phytochemicals in cancer chemoprevention. Cancer Lett. 2014 Dec;355(1):9–17. 113. Khan MI, Rath S, Adhami VM, Mukhtar H. Targeting epigenome with dietary nutrients in cancer: Current advances and future challenges. Pharmacol Res. 2018 Mar;129:375– 87. 114. Cornara L, Biagi M, Xiao J, Burlando B. Therapeutic Properties of Bioactive Compounds from Different Honeybee Products. Front Pharmacol [Internet]. 2017 Jun 28 [cited 2019 Aug 26];8:412. Available from: http://journal.frontiersin.org/article/10.3389/fphar.2017.00412/full 115. Santos-Buelga C, González-Paramás AM. Bee Products - Chemical and Biological Properties [Internet]. Alvarez-Suarez JM, editor. Bee Products - Chemical and Biological Properties. Cham: Springer International Publishing; 2017. 99–111 p. Available from: http://link.springer.com/10.1007/978-3-319-59689-1 116. Haydak MH. Honey Bee Nutrition. Annu Rev Entomol [Internet]. 1970 Jan 1;15(1):143– 56. Available from: https://doi.org/10.1146/annurev.en.15.010170.001043 117. Cridge A, Leask M, Duncan E, Dearden P. What Do Studies of Insect Polyphenisms Tell 49 Us about Nutritionally-Triggered Epigenomic Changes and Their Consequences? Nutrients [Internet]. 2015 Feb 23;7(12):1787–97. Available from: http://www.mdpi.com/2072-6643/7/3/1787 118. Dickman MJ, Kucharski R, Maleszka R, Hurd PJ. Extensive histone post-translational modification in honey bees. Insect Biochem Mol Biol. 2013 Feb;43(2):125–37. 119. Gulati P, Kohli S, Narang A, Brahmachari V. Mining histone methyltransferases and demethylases from whole genome sequence. J Biosci. 2020;45. 120. He XJ, Zhou L Bin, Pan QZ, Barron AB, Yan WY, Zeng ZJ. Making a queen: an epigenetic analysis of the robustness of the honeybee (Apis mellifera) queen developmental pathway. Mol Ecol. 2017 Mar;26(6):1598–607. 121. Lockett G, Wilkes F, Helliwell P, Maleszka R. Contrasting Effects of Histone Deacetylase Inhibitors on Reward and Aversive Olfactory Memories in the Honey Bee. Insects [Internet]. 2014 Jun 10 [cited 2020 Nov 27];5(2):377–98. Available from: http://www.mdpi.com/2075-4450/5/2/377 122. Yan H, Simola DF, Bonasio R, Liebig J, Berger SL, Reinberg D. Eusocial insects as emerging models for behavioural epigenetics. Nat Rev Genet [Internet]. 2014;15(10):677–88. Available from: https://doi.org/10.1038/nrg3787 123. Shi YY, Wu XB, Huang ZY, Wang ZL, Yan WY, Zeng ZJ. Epigenetic modification of gene expression in honey bees by heterospecific gland secretions. PLoS One. 2012;7(8):e43727. 124. Zhu K, Liu M, Fu Z, Zhou Z, Kong Y, Liang H, et al. Plant microRNAs in larval food regulate honeybee caste development. PLoS Genet. 2017 Aug;13(8):e1006946. 125. Ashby R, Forêt S, Searle I, Maleszka R. MicroRNAs in Honey Bee Caste Determination. Sci Rep [Internet]. 2016;6(1):18794. Available from: https://doi.org/10.1038/srep18794 126. Chen W-F, Wang Y, Zhang W-X, Liu Z-G, Xu B-H, Wang H-F. Methionine as a methyl donor regulates caste differentiation in the European honey bee (Apis mellifera). Insect Sci. 2020 Apr; 127. Finnin MS, Donigian JR, Cohen A, Richon VM, Rifkind RA, Marks PA, et al. Structures of a histone deacetylase homologue bound to the TSA and SAHA inhibitors. Nature. 1999 Sep;401(6749):188–93. 128. Bertrand P. Inside HDAC with HDAC inhibitors. Eur J Med Chem. 2010 Jun;45(6):2095–116. 129. Bălan A, Moga MA, Dima L, Toma S, Elena Neculau A, Anastasiu CV. Royal Jelly-A Traditional and Natural Remedy for Postmenopausal Symptoms and Aging-Related 50 Pathologies [Internet]. Vol. 25, Molecules (Basel, Switzerland). 2020. p. 3291. Available from: https://www.mdpi.com/1420-3049/25/14/3291 130. Miyata Y, Sakai H. Anti-Cancer and Protective Effects of Royal Jelly for Therapy- Induced Toxicities in Malignancies. Int J Mol Sci [Internet]. 2018 Oct 21;19(10):3270. Available from: http://www.mdpi.com/1422-0067/19/10/3270 131. Suzuki K-M, Isohama Y, Maruyama H, Yamada Y, Narita Y, Ohta S, et al. Estrogenic Activities of Fatty Acids and a Sterol Isolated from Royal Jelly. Evidence-Based Complement Altern Med [Internet]. 2008 Feb 24;5(3):295–302. Available from: http://www.hindawi.com/journals/ecam/2008/938757/ 132. Miyata Y, Araki K, Ohba K, Mastuo T, Nakamura Y, Yuno T, et al. Oral intake of royal jelly improves anti-cancer effects and suppresses adverse events of molecular targeted therapy by regulating TNF-α and TGF-β in renal cell carcinoma: A preliminary study based on a randomized double-blind clinical trial. Mol Clin Oncol. 2020 Oct;13(4):29. 133. Nakaya M, Onda H, Sasaki K, Yukiyoshi A, Tachibana H, Yamada K. Effect of Royal Jelly on Bisphenol A-Induced Proliferation of Human Breast Cancer Cells. Biosci Biotechnol Biochem [Internet]. 2007 Feb 24;71(1):253–5. Available from: http://www.tandfonline.com/doi/full/10.1271/bbb.60453 134. Moutsatsou P, Papoutsi Z, Kassi E, Heldring N, Zhao C, Tsiapara A, et al. Fatty Acids Derived from Royal Jelly Are Modulators of Estrogen Receptor Functions. Hansen IA, editor. PLoS One [Internet]. 2010 Feb 24;5(12):e15594. Available from: http://dx.plos.org/10.1371/journal.pone.0015594 135. Makino J, Ogasawara R, Kamiya T, Hara H, Mitsugi Y, Yamaguchi E, et al. Royal Jelly Constituents Increase the Expression of Extracellular Superoxide Dismutase through Histone Acetylation in Monocytic THP-1 Cells. J Nat Prod [Internet]. 2016 Apr 22 [cited 2019 Oct 30];79(4):1137–43. Available from: https://pubs.acs.org/doi/10.1021/acs.jnatprod.6b00037 77 5. Conclusions Royal jelly is a promising source of bioactive molecules for biomedical interest. Specifically, its fatty acids such as the 10-HDA and other similar molecules may be useful for new histone deacetylase inhibitors design. Our in silico data suggests that 10-HDA could interact with human HDAC2 and that it is a potential target for human carcinomas since it is up-regulated in various tumor types. 78 6. References 1. Aristizabal MJ, Anreiter I, Halldorsdottir T, Odgers CL, McDade TW, Goldenberg A, et al. Biological embedding of experience: A primer on epigenetics. Proc Natl Acad Sci [Internet]. 2020;117:23261 LP – 23269. Available from: http://www.pnas.org/content/117/38/23261.abstract 2. Hontecillas-Prieto L, Flores-Campos R, Silver A, de Álava E, Hajji N, García-Domínguez DJ. Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials [Internet]. Front. Genet. . 2020. p. 1113. Available from: https://www.frontiersin.org/article/10.3389/fgene.2020.578011 3. Yang H, Sun B, Xu K, He Y, Zhang T, Hall SRR, et al. Pharmaco-transcriptomic correlation analysis reveals novel responsive signatures to HDAC inhibitors and identifies Dasatinib as a synergistic interactor in small-cell lung cancer. EBioMedicine [Internet]. Elsevier; 2021;69. Available from: https://doi.org/10.1016/j.ebiom.2021.103457 4. Seto E, Yoshida M. Erasers of Histone Acetylation: The Histone Deacetylase Enzymes. Cold Spring Harb Perspect Biol [Internet]. 2014;6:a018713–a018713. Available from: http://cshperspectives.cshlp.org/lookup/doi/10.1101/cshperspect.a018713 5. Li G, Tian Y, Zhu W-G. The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy. Front Cell Dev Biol [Internet]. 2020;8:1004. Available from: https://www.frontiersin.org/article/10.3389/fcell.2020.576946 6. Prachayasittikul V, Prathipati P, Pratiwi R, Phanus-umporn C, Malik AA, Schaduangrat N, et al. Exploring the epigenetic drug discovery landscape. Expert Opin Drug Discov [Internet]. Taylor & Francis; 2017;12:345–62. Available from: http://dx.doi.org/10.1080/17460441.2017.1295954 7. Cheng Y, He C, Wang M, Ma X, Mo F, Yang S, et al. Targeting epigenetic regulators for cancer therapy: mechanisms and advances in clinical trials. Signal Transduct Target Ther. 2019;4:62. 8. Morel D, Jeffery D, Aspeslagh S, Almouzni G, Postel-Vinay S. Combining epigenetic drugs with other therapies for solid tumours — past lessons and future promise. Nat Rev Clin Oncol [Internet]. Nature Publishing Group; 2019 [cited 2019 Oct 8];1–17. Available from: http://www.nature.com/articles/s41571-019-0267-4 9. Milazzo G, Mercatelli D, Di Muzio G, Triboli L, De Rosa P, Perini G, et al. Histone Deacetylases (HDACs): Evolution, Specificity, Role in Transcriptional Complexes, and Pharmacological Actionability. Genes (Basel) [Internet]. MDPI; 2020;11:556. Available from: https://pubmed.ncbi.nlm.nih.gov/32429325 10. Medina-Franco JL. Epi-Informatics [Internet]. Boston: Elsevier; 2016. Available from: https://linkinghub.elsevier.com/retrieve/pii/C20140037896 11. Salvito D, Fernandez M, Jenner K, Lyon DY, de Knecht J, Mayer P, et al. Improving the Environmental Risk Assessment of Substances of Unknown or Variable Composition, Complex Reaction Products, or Biological Materials. Environ Toxicol Chem [Internet]. John Wiley & Sons, Ltd; 2020;39:2097–108. Available from: https://doi.org/10.1002/etc.4846 79 12. Maleszka R. Beyond Royalactin and a master inducer explanation of phenotypic plasticity in honey bees. Commun Biol [Internet]. 2018;1:8. Available from: https://doi.org/10.1038/s42003-017-0004-4 13. Cridge A, Leask M, Duncan E, Dearden P. What Do Studies of Insect Polyphenisms Tell Us about Nutritionally-Triggered Epigenomic Changes and Their Consequences? Nutrients [Internet]. 2015;7:1787–97. Available from: http://www.mdpi.com/2072-6643/7/3/1787 14. Chittka A, Chittka L. Epigenetics of Royalty. PLoS Biol [Internet]. 2010;8:e1000532. Available from: http://dx.plos.org/10.1371/journal.pbio.1000532 15. Dickman MJ, Kucharski R, Maleszka R, Hurd PJ. Extensive histone post-translational modification in honey bees. Insect Biochem Mol Biol. England; 2013;43:125–37. 16. Wojciechowski M, Lowe R, Maleszka J, Conn D, Maleszka R, Hurd PJ. Phenotypically distinct female castes in honey bees are defined by alternative chromatin states during larval development. Genome Res. 2018;28:1532–42. 17. Polsinelli GA, Yu HD. Regulation of histone deacetylase 3 by metal cations and 10- hydroxy-2E-decenoic acid: Possible epigenetic mechanisms of queen-worker bee differentiation. PLoS One. 2018;13:1–12. 18. Spannhoff A, Kim YK, Raynal NJ-M, Gharibyan V, Su M-B, Zhou Y-Y, et al. Histone deacetylase inhibitor activity in royal jelly might facilitate caste switching in bees. EMBO Rep [Internet]. 2011;12:238–43. Available from: http://embor.embopress.org/cgi/doi/10.1038/embor.2011.9 19. Kusaczuk M, Krętowski R, Bartoszewicz M, Cechowska-Pasko M. Phenylbutyrate-a pan- HDAC inhibitor-suppresses proliferation of glioblastoma LN-229 cell line. Tumour Biol [Internet]. 2015/08/11. Springer Netherlands; 2016;37:931–42. Available from: https://pubmed.ncbi.nlm.nih.gov/26260271 20. Göttlicher M, Minucci S, Zhu P, Krämer OH, Schimpf A, Giavara S, et al. Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells. EMBO J [Internet]. Oxford University Press; 2001;20:6969–78. Available from: https://pubmed.ncbi.nlm.nih.gov/11742974 21. Maia Assumpcao JH, Sekijima Takeda AA, Sforcin JM, Rainho CA. Brazilian propolis as a source of novel DNA methyltransferase inhibitors: A computer-aided discovery and in vitro approaches. Clin CANCER Res. 615 CHESTNUT ST, 17TH FLOOR, PHILADELPHIA, PA 19106-4404 USA: AMER ASSOC CANCER RESEARCH; 2018;24:25–6. 22. France F, Assumpção JHM, Rainho CA. Evaluation of antitumor activity of royal jelly and its compound 10-HDA in human breast cancer cell lines: perspectives for epigenetic therapy. Second AACR Int Conf Transl Cancer Med. São Paulo: AACR; 2018. 23. Assumpção JHM, Takeda AAS, Sforcin JM, Rainho CA. Effects of Propolis and Phenolic Acids on Triple-Negative Breast Cancer Cell Lines: Potential Involvement of Epigenetic Mechanisms. Molecules. 2020;25. 24. Hutter C, Zenklusen JC. The Cancer Genome Atlas: Creating Lasting Value beyond Its 80 Data. Cell [Internet]. Elsevier; 2018;173:283–5. Available from: https://doi.org/10.1016/j.cell.2018.03.042 25. Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, et al. Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. Cell [Internet]. Elsevier; 2018;173:291-304.e6. Available from: https://doi.org/10.1016/j.cell.2018.03.022 26. Aguet F, Brown AA, Castel SE, Davis JR, He Y, Jo B, et al. Genetic effects on gene expression across human tissues. Nature. Nature Publishing Group; 2017;550:204–13. 27. Aguet F, Barbeira AN, Bonazzola R, Brown A, Castel SE, Jo B, et al. The GTEx Consortium atlas of genetic regulatory effects across human tissues. bioRxiv [Internet]. Cold Spring Harbor Laboratory; 2019 [cited 2020 Feb 17];787903. Available from: https://www.biorxiv.org/content/10.1101/787903v1 28. Goldman M, Craft B, Hastie M, Repečka K, McDade F, Kamath A, et al. The UCSC Xena platform for public and private cancer genomics data visualization and interpretation. bioRxiv [Internet]. Cold Spring Harbor Laboratory; 2019 [cited 2020 Feb 17];326470. Available from: https://www.biorxiv.org/content/10.1101/326470v6 29. Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15:550. 30. Elsik CG, Tayal A, Diesh CM, Unni DR, Emery ML, Nguyen HN, et al. Hymenoptera Genome Database: integrating genome annotations in HymenopteraMine. Nucleic Acids Res. 2016;44:D793-800. 31. Wallberg A, Bunikis I, Pettersson OV, Mosbech M-B, Childers AK, Evans JD, et al. A hybrid de novo genome assembly of the honeybee, Apis mellifera, with chromosome-length scaffolds. BMC Genomics. 2019;20:275. 32. Elsik CG, Worley KC, Bennett AK, Beye M, Camara F, Childers CP, et al. Finding the missing honey bee genes: lessons learned from a genome upgrade. BMC Genomics. 2014;15:86. 33. Weinstock GM, Robinson GE, Gibbs RA, Weinstock GM, Weinstock GM, Robinson GE, et al. Insights into social insects from the genome of the honeybee Apis mellifera. Nature [Internet]. 2006;443:931–49. Available from: https://doi.org/10.1038/nature05260 34. Bateman A, Martin MJ, O’Donovan C, Magrane M, Alpi E, Antunes R, et al. UniProt: the universal protein knowledgebase. Nucleic Acids Res [Internet]. Narnia; 2017 [cited 2019 Aug 31];45:D158–69. Available from: https://academic.oup.com/nar/article- lookup/doi/10.1093/nar/gkw1099 35. Kaplan N, Linial M. ProtoBee: hierarchical classification and annotation of the honey bee proteome. Genome Res. 2006;16:1431–8. 36. Coordinators NR. Database resources of the National Center for Biotechnology Information. Nucleic Acids Res [Internet]. Oxford University Press; 2018;46:D8–13. Available from: https://pubmed.ncbi.nlm.nih.gov/29140470 81 37. Rosenbloom KR, Armstrong J, Barber GP, Casper J, Clawson H, Diekhans M, et al. The UCSC Genome Browser database: 2015 update. Nucleic Acids Res. 2015;43:D670–81. 38. Krzywinski M, Schein J, Birol I, Connors J, Gascoyne R, Horsman D, et al. Circos: an information aesthetic for comparative genomics. Genome Res. 2009;19:1639–45. 39. Madeira F, Park YM, Lee J, Buso N, Gur T, Madhusoodanan N, et al. The EMBL-EBI search and sequence analysis tools APIs in 2019. Nucleic Acids Res [Internet]. 2019;47:W636—W641. Available from: https://europepmc.org/articles/PMC6602479 40. Letunic I, Bork P. Interactive Tree Of Life (iTOL) v4: recent updates and new developments. Nucleic Acids Res [Internet]. 2019;47:W256–9. Available from: https://doi.org/10.1093/nar/gkz239 41. Waterhouse AM, Procter JB, Martin DMA, Clamp M, Barton GJ. Jalview Version 2—a multiple sequence alignment editor and analysis workbench. Bioinformatics [Internet]. 2009;25:1189–91. Available from: https://doi.org/10.1093/bioinformatics/btp033 42. Mistry J, Chuguransky S, Williams L, Qureshi M, Salazar GA, Sonnhammer ELL, et al. Pfam: The protein families database in 2021. Nucleic Acids Res. 2021;49:D412–9. 43. Blum M, Chang H-Y, Chuguransky S, Grego T, Kandasaamy S, Mitchell A, et al. The InterPro protein families and domains database: 20 years on. Nucleic Acids Res. 2021;49:D344–54. 44. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, et al. PubChem Substance and Compound databases. Nucleic Acids Res [Internet]. 2016;44:D1202–13. Available from: https://academic.oup.com/nar/article-lookup/doi/10.1093/nar/gkv951 45. Backman TWH, Cao Y, Girke T. ChemMine tools: an online service for analyzing and clustering small molecules. Nucleic Acids Res [Internet]. 2011 [cited 2019 Nov 19];39:W486– 91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21576229 46. R Core Team. R: A Language and Environment for Statistical Computing [Internet]. Vienna, Austria; 2020. Available from: https://www.r-project.org/ 47. ISO. ISO/IEC DIS 14882:2020: Programming languages - C++ [Internet]. 2020. Available from: https://www.iso.org/standard/79358.html 48. Hutchison GR, Morley C, James C, Swain C, Winter H De, Vandermeersch T. Open Babel Documentation Release 2.3.1. Open Babel [Internet]. 2011;1–151. Available from: http://openbabel.org/docs/dev/OpenBabel.pdf 49. Naveja JJ, Medina-Franco JL. Finding Constellations in Chemical Space Through Core Analysis. Front Chem. 2019;7:510. 50. Waterhouse A, Bertoni M, Bienert S, Studer G, Tauriello G, Gumienny R, et al. SWISS- MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46:W296–303. 51. Lauffer BEL, Mintzer R, Fong R, Mukund S, Tam C, Zilberleyb I, et al. Histone Deacetylase (HDAC) Inhibitor Kinetic Rate Constants Correlate with Cellular Histone Acetylation but Not 82 Transcription and Cell Viability. J Biol Chem [Internet]. 2013;288:26926–43. Available from: http://www.jbc.org/lookup/doi/10.1074/jbc.M113.490706 52. Burley SK, Berman HM, Bhikadiya C, Bi C, Chen L, Di Costanzo L, et al. RCSB Protein Data Bank: biological macromolecular structures enabling research and education in fundamental biology, biomedicine, biotechnology and energy. Nucleic Acids Res. 2019;47:D464–74. 53. Fong R, Lupardus PJ. Structure of Human HDAC2 in complex with SAHA (vorinostat). 2013; Available from: ftp://ftp.wwpdb.org/pub/pdb/data/structures/divided/pdb/lx/pdb4lxz.ent.gz 54. Pettersen EF, Goddard TD, Huang CC, Couch GS, Greenblatt DM, Meng EC, et al. UCSF Chimera: A visualization system for exploratory research and analysis. J Comput Chem [Internet]. John Wiley & Sons, Ltd; 2004 [cited 2019 Aug 31];25:1605–12. Available from: http://doi.wiley.com/10.1002/jcc.20084 55. Dos Santos RN, Ferreira LG, Andricopulo AD. Practices in Molecular Docking and Structure-Based Virtual Screening. Methods Mol Biol. United States; 2018;1762:31–50. 56. O’Boyle NM, Banck M, James CA, Morley C, Vandermeersch T, Hutchison GR. Open Babel: An open chemical toolbox. J Cheminform [Internet]. 2011;3:33. Available from: https://doi.org/10.1186/1758-2946-3-33 57. Velázquez-Libera JL, Durán-Verdugo F, Valdés-Jiménez A, Núñez-Vivanco G, Caballero J. LigRMSD: a web server for automatic structure matching and RMSD calculations among identical and similar compounds in protein-ligand docking. Bioinformatics. England; 2020;36:2912–4. 58. Kim S, Thiessen PA, Bolton EE, Chen J, Fu G, Gindulyte A, et al. PubChem Substance and Compound databases. Nucleic Acids Res [Internet]. 2016 [cited 2019 Aug 31];44:D1202–13. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26400175 59. Kim S. Getting the most out of PubChem for virtual screening. Expert Opin Drug Discov [Internet]. 2016/08/05. 2016;11:843–55. Available from: https://pubmed.ncbi.nlm.nih.gov/27454129 60. Ropp PJ, Kaminsky JC, Yablonski S, Durrant JD. Dimorphite-DL: an open-source program for enumerating the ionization states of drug-like small molecules. J Cheminform. 2019;11:14. 61. El-Gebali S, Mistry J, Bateman A, Eddy SR, Luciani A, Potter SC, et al. The Pfam protein families database in 2019. Nucleic Acids Res [Internet]. Oxford University Press; 2019 [cited 2019 Aug 31];47:D427–32. Available from: http://www.ncbi.nlm.nih.gov/pubmed/30357350 62. Kodai T, Nakatani T, Noda N. The absolute configurations of hydroxy fatty acids from the royal jelly of honeybees (Apis mellifera). Lipids. United States; 2011;46:263–70. 63. Melliou E, Chinou I. Chemistry and bioactivity of royal jelly from Greece. J Agric Food Chem. United States; 2005;53:8987–92. 64. Ramadan MF, Al-Ghamdi A. Bioactive compounds and health-promoting properties of royal jelly: A review. J Funct Foods. 2012;4:39–52. 83 65. WEAVER N, LAW JH. Heterogeneity of fatty acids from royal jelly. Nature [Internet]. England; 1960;188:938–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/13783549 66. Ahmad S, Campos MG, Fratini F, Altaye SZ, Li J. New Insights into the Biological and Pharmaceutical Properties of Royal Jelly. Int J Mol Sci. 2020;21. 67. Li X, Huang C, Xue Y. Contribution of Lipids in Honeybee ( Apis mellifera ) Royal Jelly to Health. J Med Food [Internet]. 2013 [cited 2019 Aug 26];16:96–102. Available from: http://www.ncbi.nlm.nih.gov/pubmed/23351082 68. Gregoretti I, Lee Y-M, Goodson H V. Molecular Evolution of the Histone Deacetylase Family: Functional Implications of Phylogenetic Analysis. J Mol Biol [Internet]. 2004;338:17– 31. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0022283604001408 69. Hsu K-C, Liu C-Y, Lin TE, Hsieh J-H, Sung T-Y, Tseng H-J, et al. Novel Class IIa-Selective Histone Deacetylase Inhibitors Discovered Using an in Silico Virtual Screening Approach. Sci Rep [Internet]. Nature Publishing Group UK; 2017;7:3228. Available from: https://pubmed.ncbi.nlm.nih.gov/28607401 70. Hu Y-T, Tang C-K, Wu C-P, Wu P-C, Yang E-C, Tai C-C, et al. Histone deacetylase inhibitor treatment restores memory-related gene expression and learning ability in neonicotinoid-treated Apis mellifera. Insect Mol Biol [Internet]. John Wiley & Sons, Ltd; 2018;27:512–21. Available from: https://doi.org/10.1111/imb.12390 71. Huang C-Y, Chi L-L, Huang W-J, Chen Y-W, Chen W-J, Kuo Y-C, et al. Growth stimulating effect on queen bee larvae of histone deacetylase inhibitors. J Agric Food Chem. United States; 2012;60:6139–49. 72. Terada Y, Narukawa M, Watanabe T. Specific hydroxy fatty acids in royal jelly activate TRPA1. J Agric Food Chem. United States; 2011;59:2627–35. 73. Tran TD, Ogbourne SM, Brooks PR, Sánchez-Cruz N, Medina-Franco JL, Quinn RJ. Lessons from Exploring Chemical Space and Chemical Diversity of Propolis Components. Int J Mol Sci [Internet]. MDPI; 2020;21:4988. Available from: https://pubmed.ncbi.nlm.nih.gov/32679731 74. Machado De-Melo AA, Almeida-Muradian LB de, Sancho MT, Pascual-Maté A. Composition and properties of Apis mellifera honey: A review. J Apic Res [Internet]. Taylor & Francis; 2018;57:5–37. Available from: https://doi.org/10.1080/00218839.2017.1338444 75. Alvarez-Suarez JM, Gasparrini M, Forbes-Hernández TY, Mazzoni L, Giampieri F. The Composition and Biological Activity of Honey: A Focus on Manuka Honey. Foods (Basel, Switzerland). 2014;3:420–32. 76. Kaplan M, Karaoglu Ö, Eroglu N, Silici S. Fatty Acid and Proximate Composition of Bee Bread. Food Technol Biotechnol [Internet]. University of Zagreb Faculty of Food Technology and Biotechnology; 2016;54:497–504. Available from: https://pubmed.ncbi.nlm.nih.gov/28115909 77. Dranca F, Ursachi F, Oroian M. Bee Bread: Physicochemical Characterization and Phenolic Content Extraction Optimization. Foods (Basel, Switzerland). 2020;9. 84 78. Othman ZA, Wan Ghazali WS, Noordin L, Mohd Yusof NA, Mohamed M. Phenolic Compounds and the Anti-Atherogenic Effect of Bee Bread in High-Fat Diet-Induced Obese Rats. Antioxidants (Basel, Switzerland). 2019;9. 79. Fratini F, Cilia G, Turchi B, Felicioli A. Beeswax: A minireview of its antimicrobial activity and its application in medicine. Asian Pac J Trop Med [Internet]. 2016;9:839–43. Available from: http://www.sciencedirect.com/science/article/pii/S1995764516301407 80. Münstedt K, Bogdanov S. Bee products and their potential use in modern medicine. J ApiProduct ApiMedical Sci [Internet]. 2009;1:57–63. Available from: http://www.ibra.org.uk/articles/Bee-products-and-their-potential-use-in-modern-medicine 81. Pucca MB, Cerni FA, Oliveira IS, Jenkins TP, Argemí L, Sørensen C V, et al. Bee Updated: Current Knowledge on Bee Venom and Bee Envenoming Therapy [Internet]. Front. Immunol. . 2019. p. 2090. Available from: https://www.frontiersin.org/article/10.3389/fimmu.2019.02090 82. Abd El-Wahed AA, Khalifa SAM, Sheikh BY, Farag MA, Saeed A, Larik FA, et al. Bee Venom Composition: From Chemistry to Biological Activity. In: Atta-ur-Rahman BT-S in NPC, editor. Stud Nat Prod Chem [Internet]. Elsevier; 2019. p. 459–84. Available from: http://www.sciencedirect.com/science/article/pii/B9780444641816000139 83. Kurek-Górecka A, Górecki M, Rzepecka-Stojko A, Balwierz R, Stojko J. Bee Products in Dermatology and Skin Care. Mol. . 2020. 84. Chávez-Hernández AL, Sánchez-Cruz N, Medina-Franco JL. Fragment Library of Natural Products and Compound Databases for Drug Discovery. Biomolecules. 2020;10. 85. Davison EK, Brimble MA. Natural product derived privileged scaffolds in drug discovery. Curr Opin Chem Biol. England; 2019;52:1–8. 86. Katz L, Baltz RH. Natural product discovery: past, present, and future. J Ind Microbiol Biotechnol. Germany; 2016;43:155–76. 87. Yongye AB, Waddell J, Medina-Franco JL. Molecular scaffold analysis of natural products databases in the public domain. Chem Biol Drug Des. England; 2012;80:717–24. 88. Marks PA, Rifkind RA, Richon VM, Breslow R, Miller T, Kelly WK. Histone deacetylases and cancer: causes and therapies. Nat Rev Cancer [Internet]. 2001;1:194–202. Available from: https://doi.org/10.1038/35106079 89. Luo Y, Li H. Structure-Based Inhibitor Discovery of Class I Histone Deacetylases (HDACs). Int J Mol Sci [Internet]. 2020;21:8828. Available from: https://www.mdpi.com/1422-0067/21/22/8828 90. Eckschlager T, Plch J, Stiborova M, Hrabeta J. Histone Deacetylase Inhibitors as Anticancer Drugs. Int J Mol Sci [Internet]. MDPI; 2017;18:1414. Available from: https://pubmed.ncbi.nlm.nih.gov/28671573 91. Kim B, Hong J. An overview of naturally occurring histone deacetylase inhibitors. Curr Top Med Chem [Internet]. 2015;14:2759–82. Available from: https://pubmed.ncbi.nlm.nih.gov/25487010 85 92. Berretta AA, Silveira MAD, Cóndor Capcha JM, De Jong D. Propolis and its potential against SARS-CoV-2 infection mechanisms and COVID-19 disease: Running title: Propolis against SARS-CoV-2 infection and COVID-19. Biomed Pharmacother [Internet]. 2020/08/17. The Author(s). Published by Elsevier Masson SAS.; 2020;131:110622. Available from: https://pubmed.ncbi.nlm.nih.gov/32890967 93. Shaldam MA, Yahya G, Mohamed NH, Abdel-Daim MM, Naggar Y Al. In Silico Screening of Potent Bioactive Compounds from Honey Bee Products Against COVID-19 Target Enzymes [Internet]. 2020. Available from: https://chemrxiv.org/articles/preprint/In_Silico_Screening_of_Potent_Bioactive_Compounds_ from_Honey_Bee_Products_Against_COVID-19_Target_Enzymes/12644102 94. Güler HI, Tatar G, Yildiz O, Belduz AO, Kolayli S. Investigation of potential inhibitor properties of ethanolic propolis extracts against ACE-II receptors for COVID-19 treatment by Molecular Docking Study [Internet]. 2020. Available from: https://scienceopen.com/document?vid=84428ebd-ef47-4319-89e9-eb4a180f25d5 95. Basu A, Sarkar A, Maulik U. Molecular docking study of potential phytochemicals and their effects on the complex of SARS-CoV2 spike protein and human ACE2. Sci Rep [Internet]. 2020;10:17699. Available from: https://doi.org/10.1038/s41598-020-74715-4 96. Ali MT, Blicharska N, Shilpi JA, Seidel V. Investigation of the anti-TB potential of selected propolis constituents using a molecular docking approach. Sci Rep [Internet]. Nature Publishing Group UK; 2018;8:12238. Available from: https://pubmed.ncbi.nlm.nih.gov/30116003 97. Hashem HE. IN Silico Approach of Some Selected Honey Constituents as SARS-CoV-2 Main Protease (COVID-19) Inhibitors. Eurasian J Med Oncol [Internet]. 2020;4:196–200. Available from: https://dx.doi.org/10.14744/ejmo.2020.36102 98. Duan J, Xiaokaiti Y, Fan S, Pan Y, Li X, Li X. Direct interaction between caffeic acid phenethyl ester and human neutrophil elastase inhibits the growth and migration of PANC-1 cells. Oncol Rep [Internet]. 2017 [cited 2017 Sep 13];37:3019–25. Available from: https://www.spandidos-publications.com/ 99. Habashy NH, Abu-Serie MM. The potential antiviral effect of major royal jelly protein2 and its isoform X1 against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): Insight on their sialidase activity and molecular docking. J Funct Foods [Internet]. 2020;75:104282. Available from: http://www.sciencedirect.com/science/article/pii/S1756464620305065 100. Tahir RA, Bashir A, Yousaf MN, Ahmed A, Dali Y, Khan S, et al. In Silico identification of angiotensin-converting enzyme inhibitory peptides from MRJP1. PLoS One [Internet]. Public Library of Science; 2020;15:e0228265. Available from: https://doi.org/10.1371/journal.pone.0228265 101. Ropero S, Esteller M. The role of histone deacetylases (HDACs) in human cancer. Mol Oncol [Internet]. 2007/03/07. John Wiley and Sons Inc.; 2007;1:19–25. Available from: https://pubmed.ncbi.nlm.nih.gov/19383284 102. Weichert W. HDAC expression and clinical prognosis in human malignancies. Cancer Lett. Ireland; 2009;280:168–76. 86 103. Li Y, Seto E. HDACs and HDAC Inhibitors in Cancer Development and Therapy. Cold Spring Harb Perspect Med [Internet]. 2016;6:a026831. Available from: http://perspectivesinmedicine.cshlp.org/lookup/doi/10.1101/cshperspect.a026831 104. Witt O, Deubzer HE, Milde T, Oehme I. HDAC family: What are the cancer relevant targets? Cancer Lett [Internet]. 2009;277:8–21. Available from: http://linkinghub.elsevier.com/retrieve/pii/S0304383508006496 105. Cao L-L, Song X, Pei L, Liu L, Wang H, Jia M. Histone deacetylase HDAC1 expression correlates with the progression and prognosis of lung cancer: A meta-analysis. Medicine (Baltimore). 2017;96:e7663. 106. Guo Q, Cheng K, Wang X, Li X, Yu Y, Hua Y, et al. Expression of HDAC1 and RBBP4 correlate with clinicopathologic characteristics and prognosis in breast cancer. Int J Clin Exp Pathol. 2020;13:563–72. 107. Cao L-L, Yue Z, Liu L, Pei L, Yin Y, Qin L, et al. The expression of histone deacetylase HDAC1 correlates with the progression and prognosis of gastrointestinal malignancy. Oncotarget. 2017;8:39241–53. 108. Gao D-J, Xu M, Zhang Y-Q, Du Y-Q, Gao J, Gong Y-F, et al. Upregulated histone deacetylase 1 expression in pancreatic ductal adenocarcinoma and specific siRNA inhibits the growth of cancer cells. Pancreas. United States; 2010;39:994–1001. 109. Rana Z, Diermeier S, Hanif M, Rosengren RJ. Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer. Biomedicines [Internet]. MDPI; 2020;8:22. Available from: https://pubmed.ncbi.nlm.nih.gov/32019149 110. Sharda A, Rashid M, Shah SG, Sharma AK, Singh SR, Gera P, et al. Elevated HDAC activity and altered histone phospho-acetylation confer acquired radio-resistant phenotype to breast cancer cells. Clin Epigenetics [Internet]. 2020;12:4. Available from: https://doi.org/10.1186/s13148-019-0800-4 111. Shan W, Jiang Y, Yu H, Huang Q, Liu L, Guo X, et al. HDAC2 overexpression correlates with aggressive clinicopathological features and DNA-damage response pathway of breast cancer. Am J Cancer Res [Internet]. 2017;7:1213–26. Available from: http://www.ncbi.nlm.nih.gov/pubmed/28560068 112. Müller BM, Jana L, Kasajima A, Lehmann A, Prinzler J, Budczies J, et al. Differential expression of histone deacetylases HDAC1, 2 and 3 in human breast cancer - overexpression of HDAC2 and HDAC3 is associated with clinicopathological indicators of disease progression. BMC Cancer [Internet]. 2013;13. Available from: http://bmccancer.biomedcentral.com/articles/10.1186/1471-2407-13-215 113. Zhao H, Yu Z, Zhao L, He M, Ren J, Wu H, et al. HDAC2 overexpression is a poor prognostic factor of breast cancer patients with increased multidrug resistance-associated protein expression who received anthracyclines therapy. Jpn J Clin Oncol [Internet]. 2016;46:893–902. Available from: http://www.ncbi.nlm.nih.gov/pubmed/27432453 114. Ashktorab H, Belgrave K, Hosseinkhah F, Brim H, Nouraie M, Takkikto M, et al. Global histone H4 acetylation and HDAC2 expression in colon adenoma and carcinoma. Dig Dis Sci. 87 2009;54:2109–17. 115. Ma S, Liu T, Xu L, Wang Y, Zhou J, Huang T, et al. Histone deacetylases inhibitor MS- 275 suppresses human esophageal squamous cell carcinoma cell growth and progression via the PI3K/Akt/mTOR pathway. J Cell Physiol. United States; 2019;234:22400–10. 116. Orenay-Boyacioglu S, Kasap E, Gerceker E, Yuceyar H, Demirci U, Bilgic F, et al. Expression profiles of histone modification genes in gastric cancer progression. Mol Biol Rep. Netherlands; 2018;45:2275–82. 117. Regel I, Merkl L, Friedrich T, Burgermeister E, Zimmermann W, Einwächter H, et al. Pan- histone deacetylase inhibitor panobinostat sensitizes gastric cancer cells to anthracyclines via induction of CITED2. Gastroenterology. United States; 2012;143:99-109.e10. 118. Li H, Li X, Lin H, Gong J. High HDAC9 is associated with poor prognosis and promotes malignant progression in pancreatic ductal adenocarcinoma. Mol Med Rep. 2020;21:822–32. 119. Osada H, Tatematsu Y, Saito H, Yatabe Y, Mitsudomi T, Takahashi T. Reduced expression of class II histone deacetylase genes is associated with poor prognosis in lung cancer patients. Int J cancer. United States; 2004;112:26–32. 120. Jin Z, Jiang W, Jiao F, Guo Z, Hu H, Wang L, et al. Decreased expression of histone deacetylase 10 predicts poor prognosis of gastric cancer patients. Int J Clin Exp Pathol. 2014;7:5872–9. 121. Tao X, Yan Y, Lu L, Chen B. HDAC10 expression is associated with DNA mismatch repair gene and is a predictor of good prognosis in colon carcinoma. Oncol Lett [Internet]. 2017/08/24. D.A. Spandidos; 2017;14:4923–9. Available from: https://pubmed.ncbi.nlm.nih.gov/29085502