SET oncoprotein accumulation regulates transcription through DNA demethylation and histone hypoacetylation

Autor(es)

Almeida, Luciana O. ; Neto, Marinaldo P. C. ; Sousa, Lucas O. ; Tannous, Maryna A. ; Curti, Carlos ; Leopoldino, Andreia M.

• Tipo de documento: Artigo Científico
• Fonte: ONCOTARGET; v. 8, n. 16, p. 26802-26818, APR 18 2017.
• Citações Web of Science: 6

Resumo

Epigenetic modifications are essential in the control of normal cellular processes and cancer development. DNA methylation and histone acetylation are major epigenetic modifications involved in gene transcription and abnormal events driving the oncogenic process. SET protein accumulates in many cancer types, including head and neck squamous cell carcinoma (HNSCC); SET is a member of the INHAT complex that inhibits gene transcription associating with histones and preventing their acetylation. We explored how SET protein accumulation impacts on the regulation of gene expression, focusing on DNA methylation and histone acetylation. DNA methylation profile of 24 tumour suppressors evidenced that SET accumulation decreased DNA methylation in association with loss of 5-methylcytidine, formation of 5-hydroxymethylcytosine and increased TET1 levels, indicating an active DNA demethylation mechanism. However, the expression of some suppressor genes was lowered in cells with high SET levels, suggesting that loss of methylation is not the main mechanism modulating gene expression. SET accumulation also downregulated the expression of 32 genes of a panel of 84 transcription factors, and SET directly interacted with chromatin at the promoter of the downregulated genes, decreasing histone acetylation. Gene expression analysis after cell treatment with 5-aza-2'-deoxycytidine (5-AZA) and Trichostatin A (TSA) revealed that histone acetylation reversed transcription repression promoted by SET. These results suggest a new function for SET in the regulation of chromatin dynamics. In addition, TSA diminished both SET protein levels and SET capability to bind to gene promoter, suggesting that administration of epigenetic modifier agents could be efficient to reverse SET phenotype in cancer (AU)

• Processo FAPESP: 13/10898-4 - Estudo dos mecanismos moleculares associados à proteína SET com impacto na tumorigênese e progressão do câncer oral
• Beneficiário: Carlos Curti
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 10/20536-4 - Estudo das funções da região ácida e domínio NAP da proteína SET em linhagem celular
• Beneficiário: Renata Nishida Goto
• Modalidade de apoio: Bolsas no Brasil - Iniciação Científica
• Processo FAPESP: 13/08135-2 - CTC - Centro de Terapia Celular
• Beneficiário: Dimas Tadeu Covas
• Modalidade de apoio: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 10/20384-0 - Identificação dos genes, miRNAs e proteínas regulados pela oncoproteína SET e envolvidos na malignização e progressão do carcinoma epidermóide de cabeça e pescoço usando modelo in vitro e in vivo
• Beneficiário: Andréia Machado Leopoldino
• Modalidade de apoio: Auxílio à Pesquisa - Regular
• Processo FAPESP: 09/52228-0 - Estudos da resistência à apoptose no câncer, modelo cabeça/pescoço: vias de sinalização com ênfase na PIP3-AKT/SET, estresse oxidativo, mitocôndria e correlações
• Beneficiário: Carlos Curti
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 09/10783-7 - Estudos moleculares do envolvimento das proteínas hnRNP K e SET na transcrição e tradução de proteínas associadas à tumorigênese oral
• Beneficiário: Luciana Oliveira de Almeida
• Modalidade de apoio: Bolsas no Brasil - Pós-Doutorado