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(Referência obtida automaticamente do Web of Science, por meio da informação sobre o financiamento pela FAPESP e o número do processo correspondente, incluída na publicação pelos autores.)

SIRT1 regulates Mxd1 during malignant melanoma progression

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Autor(es):
Meliso, Fabiana M. [1] ; Micali, Danilo [1] ; Silva, Camila T. [1] ; Sabedot, Thais S. [2] ; Coetzee, Simon G. [2] ; Koch, Adrian [3] ; Fahlbusch, Fabian B. [4] ; Noushmehr, Houtan [2] ; Schneider-Stock, Regine [3] ; Jasiulionis, Miriam G. [1]
Número total de Autores: 10
Afiliação do(s) autor(es):
[1] Univ Fed Sao Paulo UNIFESP, Dept Pharmacol, Ontogeny & Epigenet Lab, Sao Paulo, SP - Brazil
[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto, SP - Brazil
[3] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Pathol, Expt Tumorpathol, Erlangen - Germany
[4] Friedrich Alexander Univ Erlangen Nurnberg FAU, Dept Pediat & Adolescent Med, Erlangen - Germany
Número total de Afiliações: 4
Tipo de documento: Artigo Científico
Fonte: ONCOTARGET; v. 8, n. 70, p. 114540-114553, DEC 29 2017.
Citações Web of Science: 3
Resumo

In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, gamma H2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression. (AU)

Processo FAPESP: 15/07925-5 - Softwares de código aberto contendo ferramentas estatísticas para análise e integração de conjuntos de dados epigenômicos produzidos em alta escala, a fim de decifrar e entender redes reguladoras de câncer
Beneficiário:Houtan Noushmehr
Linha de fomento: Auxílio à Pesquisa - Apoio a Jovens Pesquisadores
Processo FAPESP: 11/12306-1 - Mecanismos epigenéticos como mediadores da transformação maligna de melanócitos associada a condições sustentadas de estresse
Beneficiário:Miriam Galvonas Jasiulionis
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 14/13663-0 - Integração de dados de expressão de genes e microRNAs, metiloma e hidroximetiloma de diferentes etapas da progressão do melanoma
Beneficiário:Miriam Galvonas Jasiulionis
Linha de fomento: Auxílio à Pesquisa - Regular
Processo FAPESP: 16/06488-3 - Análise integrativa do epigenoma de gliomas com fenótipo metilador de ilhas CpG (G-CIMP) alto e baixo: caracterização e desenvolvimento
Beneficiário:Thaís Sarraf Sabedot
Linha de fomento: Bolsas no Brasil - Doutorado Direto