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Here we show that N<jats:sup>6<\/jats:sup>-methyladenosine (m<jats:sup>6<\/jats:sup>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-\u03baB pathway. Knockdown of FTO increases m<jats:sup>6<\/jats:sup>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<jats:sup>6<\/jats:sup>A reader YTHDF2. Knockdown of FTO sensitizes melanoma cells to interferon gamma (IFN\u03b3) 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<jats:sup>6<\/jats:sup>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.<\/jats:p>","DOI":"10.1038\/s41467-019-10669-0","type":"journal-article","created":{"date-parts":[[2019,6,25]],"date-time":"2019-06-25T21:52:50Z","timestamp":1561499570000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":626,"title":["m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8970-7373","authenticated-orcid":false,"given":"Seungwon","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiangbo","family":"Wei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan-Hong","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayoung","family":"Park","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6142-5630","authenticated-orcid":false,"given":"Palak","family":"Shah","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2292-2957","authenticated-orcid":false,"given":"Yu","family":"Deng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2734-3244","authenticated-orcid":false,"given":"Andrew E.","family":"Aplin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhike","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0846-5462","authenticated-orcid":false,"given":"Seungmin","family":"Hwang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4319-7424","authenticated-orcid":false,"given":"Chuan","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2665-7962","authenticated-orcid":false,"given":"Yu-Ying","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2019,6,25]]},"reference":[{"key":"10669_CR1","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1101\/gad.191999.112","volume":"26","author":"H Tsao","year":"2012","unstructured":"Tsao, H., Chin, L., Garraway, L. 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