SIRT1 regulates Mxd1 during malignant melanoma progression

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dc.citation.issue70
dc.citation.volume8
dc.contributor.authorMeliso, Fabiana M. [UNIFESP]
dc.contributor.authorMicali, Danilo [UNIFESP]
dc.contributor.authorSilva, Camila T. [UNIFESP]
dc.contributor.authorSabedot, Thais S.
dc.contributor.authorCoetzee, Simon G.
dc.contributor.authorKoch, Adrian
dc.contributor.authorFahlbusch, Fabian B.
dc.contributor.authorNoushmehr, Houtan
dc.contributor.authorSchneider-Stock, Regine
dc.contributor.authorJasiulionis, Miriam G. [UNIFESP]
dc.coverageOrchard Park
dc.date.accessioned2020-07-02T18:52:15Z
dc.date.available2020-07-02T18:52:15Z
dc.date.issued2017
dc.description.abstractIn 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.en
dc.description.affiliationUniv Fed Sao Paulo UNIFESP, Dept Pharmacol, Ontogeny & Epigenet Lab, Sao Paulo, SP, Brazil
dc.description.affiliationUniv Sao Paulo, Ribeirao Preto Med Sch, Dept Genet, Ribeirao Preto, SP, Brazil
dc.description.affiliationFriedrich Alexander Univ Erlangen Nurnberg FAU, Inst Pathol, Expt Tumorpathol, Erlangen, Germany
dc.description.affiliationFriedrich Alexander Univ Erlangen Nurnberg FAU, Dept Pediat & Adolescent Med, Erlangen, Germany
dc.description.affiliationUnifespUniv Fed Sao Paulo UNIFESP, Dept Pharmacol, Ontogeny & Epigenet Lab, Sao Paulo, SP, Brazil
dc.description.sourceWeb of Science
dc.description.sponsorshipFAPESP [2011/0166-38, 2011/12306-1, 2014/13663-0, 2015/07925-5, 2016/06488-3]
dc.description.sponsorshipDAAD [PKZ A/12/79134]
dc.description.sponsorshipFAPESP/BAYLAT [2012/51300-7]
dc.description.sponsorshipIDFAPESP [2011/0166-38, 2011/12306-1, 2014/13663-0, 2015/07925-5, 2016/06488-3]
dc.description.sponsorshipIDDAAD [PKZ A/12/79134]
dc.description.sponsorshipIDFAPESP/BAYLAT [2012/51300-7]
dc.format.extent114540-114553
dc.identifierhttp://dx.doi.org/10.18632/oncotarget.21457
dc.identifier.citationOncotarget. Orchard Park, v. 8, n. 70, p. 114540-114553, 2017.
dc.identifier.doi10.18632/oncotarget.21457
dc.identifier.fileWOS000419571000017.pdf
dc.identifier.issn1949-2553
dc.identifier.urihttps://repositorio.unifesp.br/handle/11600/53979
dc.identifier.wosWOS:000419571000017
dc.language.isoeng
dc.publisherImpact Journals Llc
dc.relation.ispartofOncotarget
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectsirtuin-1 (SIRT1)en
dc.subjectMYC/MAX/MXD1 networken
dc.subjectepigenetic regulationen
dc.subjectmelanoma progressionen
dc.subjectDNMT3Ben
dc.titleSIRT1 regulates Mxd1 during malignant melanoma progressionen
dc.typeinfo:eu-repo/semantics/article
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