m6A 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 6 A) 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 6 A methylation in the critical protumorigenic melanoma cell-intrinsic genes including PD-1 (PDCD1), CXCR4, and SOX10, leading to increased RNA decay through the m 6 A 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 6 A 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.

Functions of N6-methyladenosine and its role in cancer

“…In melanoma, FTO impairs IFNγ-induced killing in melanoma cells in vitro via up-regulating PD-1, CXCR4, and SOX10 through suppressing YTHDF2-mediateddegradation and inhibits response to anti-PD-1 blockade immunotherapy [69].…”

The emerging roles of N6-methyladenosine (m6A) deregulation in liver carcinogenesis

“…By targeting PD1 in cytotoxic T cells or PD-L1 in cancer cells, immune checkpoint therapies activate the adaptive immune system to eliminate cancer cells. Yang et al showed that knockdown of FTO sensitizes melanoma cells to interferon gamma and anti-PD1 treatments [95]. m6A modification is also implicated in the neoantigen-specific T cell immune response.…”

m6A-binding proteins: the emerging crucial performers in epigenetics

“…In melanoma, depletion of YTHDF2 accelerated cell proliferation and migration by strikingly upregulating the mRNA levels of three key intrinsic pro-tumorigenic factors, including PD-1 (PDCD1), CXCR4, and SOX10, which was dependent on a reduced m 6 A-mediated mRNA decay [64]. Furthermore, YTHDF1 promoted the translation of tumor suppressor HINT2 mRNA which was methylated by m 6 A, thus playing a repressive role in ocular melanoma [65].…”

“…Downregulating the mRNA and protein levels of three key intrinsic pro-tumorigenic factors, including PD-1 (PDCD1), CXCR4 and SOX10 [64] YTHDF1 HINT2 Promoting the translation of HINT2 mRNA [65] Breast cancer YTHDF2 BNIP3 Facilitating the degradation of BNIP3 mRNA [66] Pancreatic cancer IGF2BP2 DANCR Enhancing the DANCR expression [67] Acute myeloid leukemia…”