Title: m6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade.
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
Published In Nat Commun, (2019 06 25)
Abstract: 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.
PubMed ID: 31239444
MeSH Terms: Adenosine/analogs & derivatives*; Adenosine/genetics; Adenosine/metabolism; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism*; Animals; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal/administration & dosage*; Carcinogenesis; Cell Line, Tumor; Cell Proliferation; DNA Methylation; Demethylation; Female; Humans; Immunotherapy; Melanoma/enzymology*; Melanoma/genetics; Melanoma/pathology; Melanoma/therapy*; Mice; Mice, Inbred C57BL; Mice, Nude; Programmed Cell Death 1 Receptor/genetics; Programmed Cell Death 1 Receptor/immunology; RNA Stability; RNA, Messenger/genetics; RNA, Messenger/metabolism