m ⁶A 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 ⁶A) 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 ⁶A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m ⁶A 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 m ⁶A 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.

Abstract

FTO is an m6A demethylase. Here, the authors show that FTO promotes melanoma tumorigenicity and contributes to resistance to anti-PD1 blockade, while FTO inhibition sensitizes melanoma to anti-PD1 blockade.