Abstract

Endometrial cancer (EC) poses a great threat to women's health worldwide. Splicing factor 3B, subunit 1 (SF3B1) and the methyltransferase Wilms tumor 1-associated protein (WTAP) have been confirmed to be involved in the progression of EC, but the relationship between them and whether they jointly regulate EC is still unclear. The mRNA and protein levels of SF3B1 and WTAP were analyzed by qRT-PCR and western blot. Then, cell proliferation, apoptosis, migration, and invasion behaviors were assessed by EdU, flow cytometry, wound healing, and Transwell assays. Bioinformatics tools were applied to predict the binding sites of WTAP on SF3B1 mRNA and the correlation between WTAP and SF3B1. The binding of the two and the m6A methylation level of SF3B1 were verified by RIP and MeRIP. Finally, the effect of WTAP/SF3B1 on EC tumors in vivo was determined by a xenograft tumor model. SF3B1 was highly expressed in EC and its knockdown inhibited the proliferation, expedited apoptosis, repressed migration and invasion, and promoted ferroptosis of EC cells. Besides, WTAP bound to SF3B1-bound mRNA and induced its m6A methylation modification. Overexpression of WTAP accelerated the malignant progression of EC cells and restrained ferroptosis. Interestingly, overexpression of SF3B1 completely abolished the tumor suppressive effect induced by WTAP knockdown. WTAP stimulated tumor growth in vivo and suppressed ferroptosis by stabilizing SF3B1 expression. In conclusion, WTAP effectively suppressed ferroptosis in EC cells by modulating SF3B1 via m6A methylation, thereby aggravating EC. Summary Knockdown of SF3B1 and WTAP effectively inhibited the malignant progression of EC. WTAP could bind to SF3B1 and induce m6A methylation modification. Overexpression of WTAP stimulated EC cell proliferation and metastasis while retarded ferroptosis. Overexpression of SF3B1 abolished the inhibitory effect of WTAP knockdown on EC cell growth. WTAP facilitated EC tumorigenesis by regulating SF3B1 in vivo