SIRT1 regulates Mxd1 during malignant melanoma progression
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Fabiana M. Meliso1,*, Danilo Micali1,*, Camila T. Silva1, Thaís S. Sabedot2, Simon G. Coetzee2, Adrian Koch3, Fabian B. Fahlbusch4, Houtan Noushmehr2, Regine Schneider-Stock3 and Miriam G. Jasiulionis1
1Ontogeny and Epigenetics Laboratory, Pharmacology Department, Universidade Federal de São Paulo - UNIFESP, São Paulo, SP, Brazil
2Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
3Experimental Tumorpathology, Institute of Pathology, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
4Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), Erlangen, Germany
*These authors share the first authorship
Miriam G. Jasiulionis, email: firstname.lastname@example.org
Keywords: sirtuin-1 (SIRT1), MYC/MAX/MXD1 network, epigenetic regulation, melanoma progression, DNMT3B
Received: July 06, 2016 Accepted: September 13, 2017 Published: October 03, 2017
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, γH2AX 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.
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