m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade

• Published in: Nature communications 2019-06, Vol.10 (1), p.1-14, Article 2782
• Main Authors: Yang, Seungwon, Wei, Jiangbo, Cui, Yan-Hong, Park, Gayoung, Shah, Palak, Deng, Yu, Aplin, Andrew E., Lu, Zhike, Hwang, Seungmin, He, Chuan, He, Yu-Ying
• Format: Article
• Language: English
• Subjects: 13/105; 13/106; 13/109; 13/2; 13/51; 13/89; 13/95; 14/1; 14/105; 14/63; 49; 49/105; 49/61; 49/91; 631/67; 631/67/1813; 631/67/1813/1634; 631/67/395; Adaptive immunity; Autophagy; Body fat; CXCR4 protein; Demethylation; DNA methylation; Humanities and Social Sciences; Immunity; Immunotherapy; Interferon; Melanoma; Mice; mRNA; multidisciplinary; N6-methyladenosine; NF-κB protein; PD-1 protein; Phagocytosis; Science; Science (multidisciplinary); Sox10 protein; Tumorigenesis; Tumorigenicity; γ-Interferon
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-10669-0

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-κB 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 (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 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. FTO is an m6A demethylase. Here, the authors show that FTO promotes melanoma tumorigenicity and contributes to resistance to anti-PD1 blockade, while FTO inhibition sensitizes melanoma to anti-PD1 blockade.