한빛사 논문
Yan-Hong Cui1,8, Seungwon Yang1,8, Jiangbo Wei2,8, Christopher R. Shea1, Wen Zhong1,3, Fang Wang1,4, Palak Shah1,7, Muhammad G. Kibriya5, Xiaolong Cui2, Habibul Ahsan5, Chuan He2,6 & Yu-Ying He1,*
1Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA. 2Departments of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA. 3Department of Radiation Oncology, 4th Affiliated Hospital, China Medical University, Shenyang, China. 4Department of Environmental Health, School of Public Health, China Medical University, Shenyang, China. 5Institute for Population and Precision Health, Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA. 6Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA. 7Present address: Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA. 8These authors contributed equally: Yan-Hong Cui, Seungwon Yang, Jiangbo Wei.
*Corresponding author
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.
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