Autophagy of the m6A mRNA demethylase FTO is impaired by low-level arsenic exposure to promote tumorigenesis

  • Nat Commun. 2021 Apr 12;12(1):2183. doi: 10.1038/s41467-021-22469-6.
Yan-Hong Cui   #  1 ,  Seungwon Yang   #  1 ,  Jiangbo Wei   #  2 ,  Christopher R Shea  1 ,  Wen Zhong  1  3 ,  Fang Wang  1  4 ,  Palak Shah  1  5 ,  Muhammad G Kibriya  6 ,  Xiaolong Cui  2 ,  Habibul Ahsan  6 ,  Chuan He  2  7 ,  Yu-Ying He  8
Affiliations
  • 1. Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA.
  • 2. Departments of Chemistry, Department of Biochemistry and Molecular Biology, Institute for Biophysical Dynamics, University of Chicago, Chicago, IL, USA.
  • 3. Department of Radiation Oncology, 4th Affiliated Hospital, China Medical University, Shenyang, China.
  • 4. Department of Environmental Health, School of Public Health, China Medical University, Shenyang, China.
  • 5. Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
  • 6. Institute for Population and Precision Health, Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
  • 7. Howard Hughes Medical Institute, University of Chicago, Chicago, IL, USA.
  • 8. Department of Medicine, Section of Dermatology, University of Chicago, Chicago, IL, USA. [email protected].
  • # Contributed equally.
PMID: 33846348 DOI: 10.1038/s41467-021-22469-6
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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