期刊
NATURE COMMUNICATIONS
卷 10, 期 -, 页码 -出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-019-10669-0
关键词
-
资金
- NIH [ES024373, ES030576, ES030546, CA225208, CA196278]
- DoD [W81XWH-18-1-0224]
- University of Chicago Comprehensive Cancer Center [P30 CA014599]
- CTSA [UL1 TR000430]
- CACHET [ES027792]
- University of Chicago Friends of Dermatology Endowment Fund
Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N-6-methyladenosine (m(6)A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. FTO level is increased in human melanoma and enhances melanoma tumorigenesis in mice. FTO is induced by metabolic starvation stress through the autophagy and NF-kappa B pathway. Knockdown of FTO increases m(6)A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m(6)A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFN gamma) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m(6)A demethylase in promoting melanoma tumorigenesis and anti-PD-1 resistance, and suggest that the combination of FTO inhibition with anti-PD-1 blockade may reduce the resistance to immunotherapy in melanoma.
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