Abstract
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.
Keywords:
CP: Cancer; arsenic; m(6)A mRNA methylation; skin cancer; translation.