한빛사 논문
Seungwon Yang1,9, Jiangbo Wei2,9, Yan-Hong Cui1,9, Gayoung Park3, Palak Shah1,4, Yu Deng1,5, Andrew E. Aplin6,7, Zhike Lu2, Seungmin Hwang3, Chuan He2,8,10,* & Yu-Ying He1,10,*
1 Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL 60637, USA. 2 Departments of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL 60637, USA. 3 Department of Pathology, University of Chicago, Chicago, IL 60637, USA. 4 Committee on Molecular Pathogenesis and Molecular Medicine, University of Chicago, Chicago, IL 60637, USA. 5 Department of Environmental Health, School of Public Health, China Medical University, Shenyang, Laoning 110122, China. 6 Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA. 7 Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USA. 8 Howard Hughes Medical Institute, University of Chicago, Chicago, IL 60637, USA. 9 These authors contributed equally: Seungwon Yang, Jiangbo Wei, Yan-Hong Cui. 10 These authors jointly supervised this work: Chuan He, Yu-Ying He.
*Correspondence and requests for materials should be addressed to Y.-Y.H.or to C.H.
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.
논문정보
관련 링크
연구자 키워드
소속기관 논문보기
관련분야 논문보기
해당논문 저자보기