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

Abstract 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…

• HH
  Howard Hughes Medical Institute
• UO
  University of Chicago

  Awards: P30 CA014599, UL1 TR000430, CA014599
• GC
  Georgia Clinical and Translational Science Alliance
• NI
  National Institutes of Health

  Awards: P30 CA014599, CA196278, UL1 TR000430, ES030576, CA225208, CA014599, W81XWH, ES030546, ES024373, TR000430, ES027792