TY - JOUR
T1 - Nuclear receptor coactivator NCOA3 regulates UV radiation⇓induced DNA damage and melanoma susceptibility
AU - de Semir, David
AU - Bezrookove, Vladimir
AU - Nosrati, Mehdi
AU - Dar, Altaf A.
AU - Miller, James R.
AU - Leong, Stanley P.
AU - Kim, Kevin B.
AU - Liao, Wilson
AU - Soroceanu, Liliana
AU - McAllister, Sean
AU - Debs, Robert J.
AU - Schadendorf, Dirk
AU - Leachman, Sancy A.
AU - Cleaver, James E.
AU - Kashani-Sabet, Mohammed
N1 - Funding Information:
This work was supported by NIH R01′s CA114337, CA175768, and CA215755 (to M. K.-Sabet), the Cancer Avatar Program Fund of the California Pacific Medical Center Foundation, and the E. A. Dickinson Emeritus Professorship of University California San Francisco (to J.E. Cleaver).
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/6/1
Y1 - 2021/6/1
N2 - 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.
AB - 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.
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U2 - 10.1158/0008-5472.CAN-20-3450
DO - 10.1158/0008-5472.CAN-20-3450
M3 - Article
C2 - 33766890
AN - SCOPUS:85106969306
VL - 81
SP - 2956
EP - 2969
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -