Autophagy of the m6A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis
Yan‐Hong Cui, Seungwon Yang, Jiangbo Wei, Christopher R. Shea, Wen Zhong, Fang Wang, Palak Shah, Muhammad G. Kibriya, Xiaolong Cui, Habibul Ahsan, Chuan He, Yu‐Ying He
Abstract
Abstract Here we show that FTO as an N 6 -methyladenosine (m 6 A) RNA demethylase is degraded by selective autophagy, which is impaired by low-level arsenic exposure to promote tumorigenesis. We found that in arsenic-associated human skin lesions, FTO is upregulated, while m 6 A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m 6 A RNA methylation, and induced malignant transformation and tumorigenesis. FTO deletion inhibited arsenic-induced tumorigenesis. Moreover, in mice, epidermis-specific FTO deletion prevented skin tumorigenesis induced by arsenic and UVB irradiation. Targeting FTO genetically or pharmacologically inhibits the tumorigenicity of arsenic-transformed tumor cells. We identified NEDD4L as the m 6 A-modified gene target of FTO. Finally, arsenic stabilizes FTO protein through inhibiting p62-mediated selective autophagy. FTO upregulation can in turn inhibit autophagy, leading to a positive feedback loop to maintain FTO accumulation. Our study reveals FTO-mediated dysregulation of mRNA m 6 A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity.