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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

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

Authors: Cui, Yan-Hong; Yang, Seungwon; Wei, Jiangbo; Shea, Christopher R; Zhong, Wen; Wang, Fang; Shah, Palak; Kibriya, Muhammad G; Cui, Xiaolong; Ahsan, Habibul; He, Chuan; He, Yu-Ying

Published In Nat Commun, (2021 Apr 12)

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.

PubMed ID: 33846348 Exiting the NIEHS site

MeSH Terms: Adenosine/analogs & derivatives*; Adenosine/metabolism; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/genetics; Alpha-Ketoglutarate-Dependent Dioxygenase FTO/metabolism*; Animals; Arsenic/toxicity*; Autophagy*/drug effects; Autophagy*/genetics; Base Sequence; Carcinogenesis/drug effects; Carcinogenesis/genetics*; Cell Transformation, Neoplastic/drug effects; Cell Transformation, Neoplastic/pathology; Down-Regulation/drug effects; Down-Regulation/genetics; Epidermis/metabolism; Gene Ontology; HEK293 Cells; HaCaT Cells; Humans; Keratinocytes/drug effects; Keratinocytes/metabolism; Lysosomes/drug effects; Lysosomes/metabolism; Mice; NF-kappa B/metabolism; Nedd4 Ubiquitin Protein Ligases/metabolism; Protein Stability/drug effects; RNA Stability/drug effects; RNA, Messenger/genetics; RNA, Messenger/metabolism; Sequestosome-1 Protein/metabolism; Transcriptome/genetics; Tumor Necrosis Factor-alpha/metabolism; Up-Regulation/drug effects; Up-Regulation/genetics; Vacuoles/drug effects; Vacuoles/metabolism; Vacuoles/ultrastructure

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