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Here, we find that METTL3, a primary m\n                    <jats:sup>6<\/jats:sup>\n                    A methyltransferase, is significantly down\u2010regulated in human sorafenib\u2010resistant hepatocellular carcinoma (HCC). Depletion of METTL3 under hypoxia promotes sorafenib resistance and expression of angiogenesis genes in cultured HCC cells and activates autophagy\u2010associated pathways. Mechanistically, we have identified FOXO3 as a key downstream target of METTL3, with m\n                    <jats:sup>6<\/jats:sup>\n                    A modification of the FOXO3 mRNA 3\u2032\u2010untranslated region increasing its stability through a YTHDF1\u2010dependent mechanism. Analysis of clinical samples furthermore showed that METTL3 and FOXO3 levels are tightly correlated in HCC patients. In mouse xenograft models, METTL3 depletion significantly enhances sorafenib resistance of HCC by abolishing the identified METTL3\u2010mediated FOXO3 mRNA stabilization, and overexpression of FOXO3 restores m\n                    <jats:sup>6<\/jats:sup>\n                    A\u2010dependent sorafenib sensitivity. Collectively, our work reveals a critical function for METTL3\u2010mediated m\n                    <jats:sup>6<\/jats:sup>\n                    A modification in the hypoxic tumor microenvironment and identifies FOXO3 as an important target of m\n                    <jats:sup>6<\/jats:sup>\n                    A modification in the resistance of HCC to sorafenib therapy.\n                  <\/jats:p>","DOI":"10.15252\/embj.2019103181","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T09:43:20Z","timestamp":1588671800000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":400,"title":["RNA m6A methylation regulates sorafenib resistance in liver cancer through FOXO3\u2010mediated autophagy"],"prefix":"10.1038","volume":"39","author":[{"given":"Ziyou","family":"Lin","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Niu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arabella","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongshi","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Liang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xijun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Siyue","family":"Zhan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liutao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chao","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianzhang","family":"Bu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiling","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5170-7282","authenticated-orcid":false,"given":"Guohui","family":"Wan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,5]]},"reference":[{"key":"BFEMBJ2019103181_CR1","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1002\/hep.30190","volume":"69","author":"MA Ardelt","year":"2019","unstructured":"Ardelt MA, Frohlich T, Martini E, Muller M, Kanitz V, Atzberger C, Cantonati P, Messner M, Posselt L, Lehr T et\u00a0al (2019) Inhibition of cyclin\u2010dependent kinase 5: a strategy to improve sorafenib response in hepatocellular carcinoma therapy. 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