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.
Highlights
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
To determine whether m6A RNA methylation and its regulators play a role in arsenic-induced tumorigenicity, we first treated HaCaT cells, a human keratinocyte cell line, continuously with a relevant low level (100 nM) of inorganic arsenite for 28 weeks to generate HaCaT cells with chronic arsenic damage (As cells)[23,24] (Supplementary Fig. 1a)
We showed that the FTO inhibitors CS1 and CS2 increased the protein and mRNA levels of NEDD4L (Supplementary Fig. 3e, f), while it had no effect on the protein or mRNA levels of FTO, consistent with the previous studies[28]
Summary
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. Chronic relevant low-level arsenic exposure upregulated FTO, downregulated m6A RNA methylation, and induced malignant transformation and tumorigenesis. RNA m6A methylation is installed by writers (methyltransferases), removed by erasers (demethylases), and recognized by readers, a piece of well-coordinated machinery to regulate m6A’s dynamics[1,2,3,4] Among these m6A effectors, FTO (fat mass and obesity-associated protein) was the first RNA m6A demethylase discovered[10] and has been shown to play oncogenic roles in leukemia[11], glioblastoma[12], and melanoma[13]. We discovered that chronic low-level arsenic exposure upregulates FTO and downregulates m6A RNA methylation in keratinocytes, and induces malignant transformation and tumorigenesis through FTO and m6A mRNA methylation. FTO forms a positive feedback loop with autophagy inhibition to maintain FTO accumulation in arsenic tumorigenesis Taken together, these results demonstrate that m6A RNA methylation acts as an epitranscriptomic mechanism for arsenic damage response and tumorigenesis
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