DNA修复
平方毫米
化学
癌变
细胞生物学
DNA
分子生物学
作者
David de Semir,Vladimir Bezrookove,Mehdi Nosrati,Altaf A. Dar,James R. Miller,Stanley P.L. Leong,Kevin B. Kim,Wilson Liao,Liliana Soroceanu,Sean D. McAllister,Robert J. Debs,Dirk Schadendorf,Sancy A. Leachman,James E. Cleaver,Mohammed Kashani-Sabet
出处
期刊:Cancer Research
[American Association for Cancer Research]
日期:2021-06-01
卷期号:81 (11): 2956-2969
标识
DOI:10.1158/0008-5472.can-20-3450
摘要
Melanoma occurs as a consequence of inherited susceptibility to the disease and exposure to ultraviolet 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 single nucleotide polymorphism 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 in the setting of UVR exposure, enabling enhanced melanocyte survival despite an increased mutational burden. They also identify NCOA3 as a novel therapeutic target for melanoma.
科研通智能强力驱动
Strongly Powered by AbleSci AI