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 and Yu-Ying He ()
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Yan-Hong Cui: University of Chicago
Seungwon Yang: University of Chicago
Jiangbo Wei: University of Chicago
Christopher R. Shea: University of Chicago
Wen Zhong: University of Chicago
Fang Wang: University of Chicago
Palak Shah: University of Chicago
Muhammad G. Kibriya: The University of Chicago
Xiaolong Cui: University of Chicago
Habibul Ahsan: The University of Chicago
Chuan He: University of Chicago
Yu-Ying He: University of Chicago

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract Here we show that FTO as an N6-methyladenosine (m6A) 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 m6A RNA methylation is downregulated. In keratinocytes, chronic relevant low-level arsenic exposure upregulated FTO, downregulated m6A 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 m6A-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 m6A methylation as an epitranscriptomic mechanism to promote arsenic tumorigenicity.

Date: 2021
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DOI: 10.1038/s41467-021-22469-6

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