Arsenic regulates ALKBH1 abundance and substrate specificity to promote translation and tumorigenicity

The mechanisms that underlie arsenic tumorigenicity remain incompletely understood. Here, we show that arsenic regulates the abundance and the demethylase activity of ALKBH1, which, in turn, promotes arsenic-induced skin tumorigenesis. At the molecular level, knockdown of ALKBH1 in arsenic-exposed keratinocytes increases m⁶A enrichment in mRNA, and ALKBH1 demethylates m⁶A in vitro in an arsenic-dependent manner. Arsenic binds to the ALKBH1 protein at cysteine residues to regulate the m⁶A RNA demethylase activity of ALKBH1. m⁶A-immunoprecipitation (IP)-sequencing demonstrates that ALKBH1 regulates m⁶A demethylation on the NR2C2 transcript to inhibit NR2C2 protein translation in a YTHDF1-dependent manner. Functionally, knockdown of ALKBH1 increases NR2C2 expression, leading to decreased mTOR activation and global translation. Our work uncovers a previously unknown mechanism into arsenic tumorigenicity, adds understanding into the functional effect of arsenic binding to proteins, and implicates ALKBH1 as a potential druggable target and biomarker for arsenic tumorigenicity.