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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

SIRT1 regulates Mxd1 during malignant melanoma progression

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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]
Total Authors: 10
[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
Total Affiliations: 4
Document type: Journal article
Source: ONCOTARGET; v. 8, n. 70, p. 114540-114553, DEC 29 2017.
Web of Science Citations: 4

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)

FAPESP's process: 15/07925-5 - Open source software statistical tools to aid in analyzing and integrating large cancer epigenomic datasets in order to decipher and understand regulatory networks
Grantee:Houtan Noushmehr
Support type: Research Grants - Young Investigators Grants
FAPESP's process: 11/12306-1 - Epigenetic mechanisms as mediators of melanocyte malignant transformation associated with sustained stress condition
Grantee:Miriam Galvonas Jasiulionis
Support type: Regular Research Grants
FAPESP's process: 14/13663-0 - Integrating gene and microRNA expression, methylome and hidroxymethylome data from different phases of melanoma progression.
Grantee:Miriam Galvonas Jasiulionis
Support type: Regular Research Grants
FAPESP's process: 16/06488-3 - Integrative epigenomic analysis of high and low Glioma-CpG island Methylator Phenotype (G-CIMP): characterization and methods development
Grantee:Thaís Sarraf Sabedot
Support type: Scholarships in Brazil - Doctorate (Direct)