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WTAP participates in the DNA damage response via an m6A-FOXM1-dependent manner in hepatocellular carcinoma

Year: 2025

Type: article

Abstract: N6-Methyladenosine (m6A) is one of the most abundant RNA modifications that occur in eukaryotes. The relationship between m6A methylation and DNA damage repair (DDR) is still unclear. As an important chaperone protein of m6A methyltransferase, the role of Wilm’s tumor–associated protein (WTAP) in DDR has not been studied in detail. We identified that WTAP was markedly upregulated in HCC cells with DNA damage induction. Further investigations revealed that WTAP was engaged in DDR and WTAP knockdown resulted in a significant decrease of the stability of the DDR-related transcription factor Forkhead Box M1 (FOXM1) mRNA, eventually preventing DDR. WTAP deficiency inhibited cell growth both in vivo and in vitro. Moreover, WTAP silencing sensitized HCC cells to cisplatin, a well-known DNA damage agent. Altogether, our findings demonstrate that WTAP is the dominant m6A -related modulator upon DNA damage and functions by stabilizing FOXM1. In addition, WTAP deficiency saliently sensitized HCC cells to cisplatin both in vitro and in vivo.

Source: Cell Death Discovery

DOI: 10.1038/s41420-025-02639-x