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

Seungwon Yang, Jiangbo Wei, Yan-Hong Cui, Gayoung Park, Palak Shah, Yu Deng, Andrew E. Aplin, Zhike Lu, Seungmin Hwang, Chuan He () and Yu-Ying He ()
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Seungwon Yang: University of Chicago
Jiangbo Wei: University of Chicago
Yan-Hong Cui: University of Chicago
Gayoung Park: University of Chicago
Palak Shah: University of Chicago
Yu Deng: University of Chicago
Andrew E. Aplin: Thomas Jefferson University
Zhike Lu: University of Chicago
Seungmin Hwang: University of Chicago
Chuan He: University of Chicago
Yu-Ying He: University of Chicago

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-10669-0

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