M6A mRNA demethylase FTO regulates melanoma tumorigenicity and response to anti-PD-1 blockade

Seungwon Yang,Zhike Lu,Andrew E Aplin,Yan-Hong Cui,Jiangbo Wei,Yu-Ying He,Chuan He,Yu Deng,Palak Shah,Gayoung Park,Seungmin Hwang

doi:10.1038/s41467-019-10669-0

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.

Highlights

Melanoma is one of the most deadly and therapy-resistant cancers
fat mass and obesity-associated protein (FTO) can be upregulated by metabolic stress and starvation, a metabolic challenge that tumor cells are constantly facing in vivo, suggesting that the induction of FTO serves as an adaptive mechanism to metabolic stress in melanoma cells to promote proliferation, invasion, and migration
FTO knockdown increases m6A enrichment in the critical melanomapromoting genes including PD-1 (PDCD1), CXCR4, and SOX10, and decreases their messenger RNA (mRNA) stability

Summary

Introduction

Melanoma is one of the most deadly and therapy-resistant cancers. Here we show that N6methyladenosine (m6A) mRNA demethylation by fat mass and obesity-associated protein (FTO) increases melanoma growth and decreases response to anti-PD-1 blockade immunotherapy. Tremendous progress has been made in elucidating the mechanism of melanoma development at the molecular, cellular and organismal levels[1] Both genetic, including mutations in oncogenes and tumor suppressor genes, and epigenetic mechanisms, including DNA methylation, microRNAs, and other non-coding RNAs, have been demonstrated to play critical roles in melanoma pathogenesis[1,3,4,5]. Two studies independently mapped the transcriptome-wide m6A distribution[17,18] These studies suggest that, similar to the reversible epigenetic modifications to DNA and histone, posttranscriptional methylation of adenosines in RNA provides an epitranscriptomic layer of regulation that may control mRNA fate and gene expression. We report that the m6A demethylase FTO regulates melanoma growth and mediates melanoma resistance to anti-PD-

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