YTHDF2 promotes arsenic-induced malignant phenotypes by degrading PIDD1 mRNA in human keratinocytes

Arsenic is a widespread environmental carcinogen, and its carcinogenic mechanism has been the focus of toxicology. N⁶-methyladenosine (m⁶A) binding protein YTH domain family protein 2 (YTHDF2) performs various biological functions by degrading m⁶A-modified mRNAs. However, the m⁶A-modified target mRNA of YTHDF2 in regulating arsenic carcinogenesis remains largely unknown. To explore the effect of YTHDF2 in regulating arsenic carcinogenicity, we exposed the human keratinocyte HaCaT cells to 1 μM sodium arsenite for 50 generations to create a cell model of arsenic carcinogenesis (HaCaT-T). Our results demonstrated that YTHDF2 protein levels were higher in HaCaT-T cells than HaCaT cells, and knockdown of YTHDF2 significantly inhibited arsenic-induced malignant phenotypes. In addition, m⁶A levels in HaCaT-T cells were remarkably elevated, accompanied by abnormal expression of m⁶A methyltransferases and m⁶A demethylases. Mechanistically, YTHDF2 bound to p53-induced death domain protein 1 (PIDD1) mRNA in an m⁶A-dependent manner, thereby promoting the degradation of PIDD1 mRNA. Moreover, the decay of PIDD1 mRNA inhibited the formation of PIDDosome complex that is essential for activating the apoptosis initiator caspase-2, leading to a decrease in caspase-2-dependent mitochondrial apoptosis and subsequently promoting the malignant phenotypes of HaCaT-T cells. Collectively, our study reveals the role of YTHDF2 in arsenic-induced malignant phenotypes of human keratinocytes through direct interaction with PIDD1 mRNA in an m⁶A-dependent manner, which provides new insight into the precise mechanism underlying arsenic-induced skin cancer.