WTAP Regulates SOX1 Expression to Affect the Tumorigenicity of Colorectal Cancer via an m⁶A-YTHDF2-Dependent Manner

Background: Wilms tumor 1-associated protein (WTAP) plays a critical role in various cancers, including colorectal cancer (CRC). However, the biological function and molecular mechanisms of WTAP in CRC remain to be elucidated.

Methods: We determined the expression of WTAP and its correlation with unfavorable prognosis of CRC using RNA-seq and the UALCAN dataset. And we investigated the effects of WTAP on CRC cells using cell proliferation assay, colony formation, cell migration and invasion, and subcutaneous xenograft experiments. We then knockdown of WTAP to identify candidate targets of WTAP. Moreover, the mRNA stability of SRY-box transcription factor 1 (SOX1) was assessed by overexpressing YTHDF2. Finally, we investigated the regulatory mechanism of WTAP in CRC by MeRIP assay, RNA pulldown, dual-luciferase reporter assay, and RIP assay.

Results: We demonstrated that CRC patients with a high expression of WTAP have a risk prognosis. Additionally, WTAP expression can serve as a predictor of survival in CRC. WTAP promoted the proliferation and tumor growth of CRC cells. Moreover, WTAP has been recognized as the upstream regulator of SOX1. WTAP regulated the m⁶A modification, resulting in the post-transcriptional inhibition of SOX1. YTHDF2 plays a role in promoting mRNA degradation. Then, SOX1 can hinder the progression of CRC. Furthermore, WTAP can regulate the proliferation, migration, and invasion of CRC cells by SOX1 via an m⁶A-YTHDF2-dependent manner.

Conclusion: Our findings demonstrate that WTAP-mediated m⁶A modification facilitated the progression of CRC through the YTHDF2-SOX1 axis and could serve as a potential therapeutic targeting for CRC.