Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6-methyladenosine (m6A) 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-κB pathway. Knockdown of FTO increases m6A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m6A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFNγ) and sensitizes melanoma to anti-PD-1 treatment in mice, depending on adaptive immunity. Our findings demonstrate a crucial role of FTO as an m6A 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. © 2019, The Author(s).
Recommended CitationYang, Seungwon; Wei, Jiangbo; Cui, Yan-Hong; Park, Gayoung; Shah, Palak; Deng, Yu; Aplin, Andrew E.; Lu, Zhike; Hwang, Seungmin; He, Chuan; and He, Yu-Ying, "m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade" (2019). Department of Cancer Biology Faculty Papers. Paper 153.
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