For the first time, the activity of nuclear receptor coactivator 3 (NCOA3) has been shown to promote melanoma development through ultraviolet radiation (UVR) sensitivity regulation, cell cycle progression and circulating DNA damage response. The results of a preclinical study led by Mohammed Kashani-Sabet, MD, Medical Director of the Cancer Center at California Pacific Sutter Medical Center (CPMC) in San Francisco, CA were published online today in Cancer research, journal of the American Society for the Study of Cancer.
“Our research suggests an unprecedented way in which NCOA3 regulates the DNA damage response and acts as a potential therapeutic target in melanoma, where NCOA3 activity contributes to melanoma development. after being exposed to ultraviolet light, ”said Dr. Kashani-Sabet, who collaborated with scientists at the CPMC Research Institute, the University of Duisburg-Essen in Germany and the Knight Cancer Institute in Portland, OR for the study.
Epidemiological studies suggest a place for UVR in the cause of melanoma, supported by whole-genome sequencing studies revealing a high burden of signature UV rays. But the exact molecular mechanisms by which melanoma develops after UVR are not yet properly understood, so it is necessary to identify additional molecular factors that regulate both UV and melanoma susceptibility.
NCOA3 (also known as AIB1 or SRC-3) is a member of the nuclear hormone receptor coactivator family, and regulates gene expression through its interaction with various transcription factors. NCOA3 has been shown to be initially increased in breast cancer, and an oncogenic role has been shown in several solid tumors. However, a role for NCOA3 in melanomagenesis by UVR medium has not been previously demonstrated.
Using a combination of in vitro, in vivo and PDX modeling of melanomagenesis, Dr. Kashani and colleagues evaluated the effects of NCOA3 expression regulation in human melanoma cells as well as in melanocytes, identifying several oncogenic pathways. regulated by NCOA3 in melanoma progression.
Results showed that sub-regulation of NCOA3 expression, either by genetic disruption or by small molecular inhibition, significantly contributed to melanoma reduction in melanoma cell lines and PDXs. NCOA3 suppresses saturated expression of xeroderma pigmentosum C and increased sensitivity of melanoma cells to UVR. Expression of NCOA3 expression activated DDR receptors and reduced sensitivity of cyclin B1, leading to G2 / M arrest and mitotic catastrophe.
One nucleotide polymorphism in NCOA3 (T960T) was associated with reduced melanoma risk, as the incidence was significantly lower in the familial melanoma cohort than in the non-cancer control cohort. Further studies suggest that this polymorphism reduces NCOA3 protein production, and in combination with increased sensitivity to ultraviolet light – leads to cell death.
Taken together, these findings are consistent with a model of melanoma onset in which elevated NCOA3 expression promotes melanocyte survival after exposure to UVR. This survival advantage enables UVR-mediated DNA damage to accumulate. Over the life of a person susceptible to melanoma, excessive exposure to UVR can lead to both the high mutational burden and unregulated cell proliferation that characterizes the disease. In contrast, these effects are reduced after expression of T960T polymorphism, with increased sensitivity to UV-mediated cell death, thus protecting against UVR carcinogenic effects.
Our results highlight an unprecedented place for molecular signaling at specific levels of tumor progression. These results identify NCOA3 as a candidate vulnerability marker for melanoma, as a potential diagnostic marker, as a prognostic marker of melanoma survival and as a target for treatment. We propose an essential role for NCOA3 in UVR-mediated melanomagenesis, and as a reasonable therapeutic target for melanoma. “
Dr. Mohammed Kashani-Sabet, Medical Director of the Cancer Center, California Pacific Sutter Medical Center (CPMC), San Francisco, CA
Skin cancer is the most common type of cancer worldwide. Melanoma makes up about 1% of skin cancers but causes the majority of skin cancer deaths. This year, approximately 106,000 Americans will be diagnosed with melanoma.
“We are committed to advancing this research to help guide and inform care for the treatment of Sutter patients with melanoma and other patients worldwide,” said Dr. Kashani-Sabet.
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Magazine Reference:
of Semir, D., et al. (2021) NCOA3 nuclear receptor coactivator regulates ultraviolet radiation-induced DNA damage and melanoma vulnerability. Cancer research. doi.org/10.1158/0008-5472.CAN-20-3450.