Avaliação da acetilação das histonas H3 e H4 e expressão das enzimas histonas desacetilases HDAC1, HDAC2 e HDAC6 no linfoma multicêntrico canino
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Data
2021-11-08
Autores
Canavari, Isabela Cristina
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Universidade Estadual Paulista (Unesp)
Resumo
Alterações epigenéticas são associadas aos processos de carcinogênese e a acetilação das histonas é um dos mecanismos mais estudados, ocorrendo de acordo com a atividade das enzimas histonas acetilases (HAT) e histonas desacetilases (HDAC). O aumento na expressão e/ou atuação aberrante das HDAC interferem diretamente na regulação transcricional, podem fornecer condições para o desenvolvimento tumoral e tornaram-se alvos de estudos para intervenção terapêutica. No linfoma difuso de grandes células B (LDGCB), em humanos, alterações nos mecanismos epigenéticos de acetilação das histonas já foram identificadas e associadas ao pior prognóstico dos pacientes. Porém, em cães ainda são escassos os estudos que avaliaram essas modificações na forma multicêntrica do LDGCB. No primeiro capítulo, são descritos os mecanismos epigenéticos relacionados aos seus aspectos fisiológicos e as modificações registradas em neoplasias, nas medicinas humana e veterinária. No segundo capítulo, foram avaliadas as expressões das histonas acetiladas H3 e H4, e das enzimas HDAC1, HDAC2 e HDAC6 em amostras de LDGCB (n=20), comparativamente à expressão em tecido linfóide de cães saudáveis (n=5), por meio da marcação imuno-histoquímica e validação da expressão proteica por Western blot. As expressões das histonas e enzimas e os aspectos clínico-patológicos foram correlacionados entre si e com o prognóstico dos animais doentes. Os resultados mostraram que HDAC2 está mais expressa no LDGCB (p < 0,05), enquanto H3, H4, HDAC1 e HDAC6 não diferiram entre os grupos. As histonas acetiladas e enzimas histonas desacetilases não apresentaram correlação com o tempo livre de doença (TLD) e tempo de sobrevida (TS), porém o alto índice mitótico foi relacionado ao menor tempo de sobrevida dos cães e menor expressão de HDAC6; e a presença de sinais clínicos no estadiamento da doença (subestágio b) indicou menores TLD e TS. Esse estudo deve estimular o desenvolvimento de novas investigações, a fim de melhor elucidar as alterações epigenéticas na patogênese do LDGCB, uma das neoplasias mais comuns em cães, podendo auxiliar na descoberta de novas abordagens terapêuticas alvo-específicas e melhorando o prognóstico dos pacientes.
Epigenetic alterations are associated with carcinogenesis processes and histone acetylation is one of the most studied mechanisms, occurring according to the activity of histone acetylase (HAT) and histone deacetylase (HDAC) enzymes. The increased expression and/or aberrant action of HDACs directly interfere with transcriptional regulation, may provide conditions for tumor development and become targets of studies for therapeutic intervention. In diffuse large B-cell lymphoma (DLBCL) in humans, alterations in the epigenetic mechanisms of histone acetylation have been identified and associated with a worse prognosis in patients. However, in dogs, there are few studies that evaluated these changes in the multicentric form of the DLBCL. The first chapter describes the epigenetic mechanisms related to their physiological aspects and the changes recorded in neoplasms, in human and veterinary medicine. In the second chapter, the expression of acetylated histones H3 and H4, and of the enzymes HDAC1, HDAC2 and HDAC6 in DLBCL samples (n=20) were evaluated and compared to the expression in lymphoid tissue of healthy dogs (n=5), through of immunohistochemical labeling and validation of protein expression by Western blot. Histone and enzyme expressions and clinicopathological aspects were correlated with each other and with the prognosis of the sick animals. The results showed that HDAC2 is more expressed in DLBCL (p < 0.05), while H3, H4, HDAC1 and HDAC6 did not differ between groups. The acetylated histones and histone deacetylase enzymes did not correlate with disease-free time (DFT) and survival time (ST), but the high mitotic index was related to the shorter survival time of dogs and lower expression of HDAC6; and the presence of clinical signs in the stage of the disease (substage b) indicated lower DFT and ST. This study should stimulate the development of new investigations, in order to better elucidate the epigenetic alterations in the pathogenesis of DLBCL, one of the most common neoplasms in dogs, which may help in the discovery of new target-specific therapeutic approaches and improve the prognosis of the patients.
Epigenetic alterations are associated with carcinogenesis processes and histone acetylation is one of the most studied mechanisms, occurring according to the activity of histone acetylase (HAT) and histone deacetylase (HDAC) enzymes. The increased expression and/or aberrant action of HDACs directly interfere with transcriptional regulation, may provide conditions for tumor development and become targets of studies for therapeutic intervention. In diffuse large B-cell lymphoma (DLBCL) in humans, alterations in the epigenetic mechanisms of histone acetylation have been identified and associated with a worse prognosis in patients. However, in dogs, there are few studies that evaluated these changes in the multicentric form of the DLBCL. The first chapter describes the epigenetic mechanisms related to their physiological aspects and the changes recorded in neoplasms, in human and veterinary medicine. In the second chapter, the expression of acetylated histones H3 and H4, and of the enzymes HDAC1, HDAC2 and HDAC6 in DLBCL samples (n=20) were evaluated and compared to the expression in lymphoid tissue of healthy dogs (n=5), through of immunohistochemical labeling and validation of protein expression by Western blot. Histone and enzyme expressions and clinicopathological aspects were correlated with each other and with the prognosis of the sick animals. The results showed that HDAC2 is more expressed in DLBCL (p < 0.05), while H3, H4, HDAC1 and HDAC6 did not differ between groups. The acetylated histones and histone deacetylase enzymes did not correlate with disease-free time (DFT) and survival time (ST), but the high mitotic index was related to the shorter survival time of dogs and lower expression of HDAC6; and the presence of clinical signs in the stage of the disease (substage b) indicated lower DFT and ST. This study should stimulate the development of new investigations, in order to better elucidate the epigenetic alterations in the pathogenesis of DLBCL, one of the most common neoplasms in dogs, which may help in the discovery of new target-specific therapeutic approaches and improve the prognosis of the patients.
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Cães, Linfoma, Oncologia, Epigenética