SRSF9 Forms Phase-separated Condensates to Promote Ovarian Cancer Progression by Inducing RNA Alternative Splicing that is Inhibited by m6A Modification

Abstract Deregulation of RNA alternative splicing and modification can play an important role in tumor initiation and progression. Elucidation of the interplay between alternative splicing and modifications of RNA could provide important insights into cancer biology. Here, we showed that serine/arginine-rich splicing factor 9 (SRSF9) recognized non-N6-methyladenosine (m6A)-modified NUMB mRNA and induced an oncogenic isoform switch in ovarian cancer (OC). NUMB mRNA m6A modification antagonized SRSF9-mediated alternative splicing. Notably, SRSF9 formed phase-separated condensates within the nucleus, which was indispensable for its splicing function as well as tumor-promoting effect in OC. Furthermore, SRSF9 was aberrantly upregulated in OC, correlating with poor patient prognosis. Loss of SRSF9 or antisense oligonucleotides-mediated isoform switch of NUMB mRNA inhibited OC growth in vitro and in vivo. In conclusion, this study reveals that SRSF9 condensation promotes OC progression through modulation of alternative splicing, in competition with m6A modification.