癌变
下调和上调
脱甲基酶
自噬
甲基化
化学
生物
RNA甲基化
N6-甲基腺苷
癌症研究
甲基转移酶
细胞生物学
砷
表观遗传学
生物化学
基因
细胞凋亡
有机化学
作者
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
标识
DOI:10.1038/s41467-021-22469-6
摘要
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.
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