IGF2BP3 recruits NUDT21 to regulate SPTBN1 alternative polyadenylation and drive ovarian cancer progression.

Ovarian cancer (OC) is one of the deadliest gynecological malignancies. As the prevalent post-transcriptional regulation, alternative polyadenylation (APA) plays a crucial role in various tumors. Here we identify that the APA regulator NUDT21 is upregulated in OC and promotes malignant progression. We further demonstrate that IGF2BP3 interacts with NUDT21, which suggests m6A modification could regulate APA processing. Mechanistically, IGF2BP3, recognizing the m6A-modified site in intron 32 of SPTBN1, recruits NUDT21 to promote the usage of the SPTBN1 proximal polyadenylation site (PAS), thus increasing the generation of short transcripts in OC cells. Intriguingly, the SPTBN1 long variant demonstrates tumor-suppressive properties, whereas the short variant enhances oncogenic activity in OC. Subsequently, we illustrate that the long isoform inhibits tumor growth and metastasis by binding to CDK1 and blocking the G2/M phase of the cell cycle. In conclusion, this study uncovers a previously unrecognized regulatory mechanism in OC, which could provide potential therapeutic strategies for OC.