Nuclear receptor coactivator NCOA3 regulates UV radiation⇓induced DNA damage and melanoma susceptibility

David de Semir, Vladimir Bezrookove, Mehdi Nosrati, Altaf A. Dar, James R. Miller, Stanley P. Leong, Kevin B. Kim, Wilson Liao, Liliana Soroceanu, Sean McAllister, Robert J. Debs, Dirk Schadendorf, Sancy A. Leachman, James E. Cleaver, Mohammed Kashani-Sabet

Research output: Contribution to journalArticlepeer-review

Abstract

Melanoma occurs as a consequence of inherited susceptibility to the disease and exposure to UV radiation (UVR) and is characterized by uncontrolled cellular proliferation and a high mutational load. The precise mechanisms by which UVR contributes to the development of melanoma remain poorly understood. Here we show that activation of nuclear receptor coactivator 3 (NCOA3) promotes melanomagenesis through regulation of UVR sensitivity, cell-cycle progression, and circumvention of the DNA damage response (DDR). Downregulation of NCOA3 expression, either by genetic silencing or small-molecule inhibition, significantly suppressed melanoma proliferation in melanoma cell lines and patient-derived xenografts. NCOA3 silencing suppressed expression of xeroderma pigmentosum C and increased melanoma cell sensitivity to UVR. Suppression of NCOA3 expression led to activation of DDR effectors and reduced expression of cyclin B1, resulting in G2-M arrest and mitotic catastrophe. A SNP in NCOA3 (T960T) reduced NCOA3 protein expression and was associated with decreased melanoma risk, given a significantly lower prevalence in a familial melanoma cohort than in a control cohort without cancer. Overexpression of wild-type NCOA3 promoted melanocyte survival following UVR and was accompanied by increased levels of UVR-induced DNA damage, both of which were attenuated by overexpression of NCOA3 (T960T). These results describe NCOA3-regulated pathways by which melanoma can develop, with germline NCOA3 polymorphisms enabling enhanced melanocyte survival in the setting of UVR exposure, despite an increased mutational burden. They also identify NCOA3 as a novel therapeutic target for melanoma.

Original languageEnglish (US)
Pages (from-to)2956-2969
Number of pages14
JournalCancer Research
Volume81
Issue number11
DOIs
StatePublished - Jun 1 2021

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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