Nuclear Receptor Coactivator NCOA3 Regulates UV Radiation-Induced DNA Damage and Melanoma Susceptibility.

Autor: de Semir D; Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California.; California Pacific Medical Center Research Institute, San Francisco, California., Bezrookove V; Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California.; California Pacific Medical Center Research Institute, San Francisco, California., Nosrati M; Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California.; California Pacific Medical Center Research Institute, San Francisco, California., Dar AA; Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California.; California Pacific Medical Center Research Institute, San Francisco, California., Miller JR 3rd; Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California.; California Pacific Medical Center Research Institute, San Francisco, California., Leong SP; Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California.; California Pacific Medical Center Research Institute, San Francisco, California., Kim KB; Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California.; California Pacific Medical Center Research Institute, San Francisco, California., Liao W; Department of Dermatology, University of California San Francisco, San Francisco, California., Soroceanu L; California Pacific Medical Center Research Institute, San Francisco, California., McAllister S; California Pacific Medical Center Research Institute, San Francisco, California., Debs RJ; California Pacific Medical Center Research Institute, San Francisco, California., Schadendorf D; Department of Dermatology, University Duisburg-Essen, Essen, Germany.; German Cancer Consortium (DKTK), Heidelberg, Germany., Leachman SA; Department of Dermatology and Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon., Cleaver JE; Department of Dermatology, University of California San Francisco, San Francisco, California., Kashani-Sabet M; Center for Melanoma Research and Treatment, California Pacific Medical Center Research Institute, San Francisco, California. kashani@cpmcri.org.; California Pacific Medical Center Research Institute, San Francisco, California.
Jazyk: angličtina
Zdroj: Cancer research [Cancer Res] 2021 Jun 01; Vol. 81 (11), pp. 2956-2969. Date of Electronic Publication: 2021 Mar 25.
DOI: 10.1158/0008-5472.CAN-20-3450
Abstrakt: 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 G 2 -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. SIGNIFICANCE: This study explores NCOA3 as a regulator of the DDR and a therapeutic target in melanoma, where activation of NCOA3 contributes to melanoma development following exposure to ultraviolet light.
(©2021 American Association for Cancer Research.)
Databáze: MEDLINE
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