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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
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
Substances
-
NF-kappa B
-
RNA, Messenger
-
SQSTM1 protein, human
-
Sequestosome-1 Protein
-
Tumor Necrosis Factor-alpha
-
N-methyladenosine
-
Alpha-Ketoglutarate-Dependent Dioxygenase FTO
-
FTO protein, human
-
Nedd4 Ubiquitin Protein Ligases
-
Nedd4L protein, human
-
Adenosine
-
Arsenic