Hongyan Zhao

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. In this study, 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. 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 its tumor-promoting effect in ovarian cancer. Furthermore, SRSF9 was aberrantly upregulated in ovarian cancer, correlating with poor patient prognosis. Loss of SRSF9 or antisense oligonucleotide–mediated isoform switch of NUMB mRNA inhibited ovarian cancer growth in vitro and in vivo. In conclusion, this study reveals that SRSF9 condensation promotes ovarian cancer progression through modulation of alternative splicing, in competition with m6A modification. Significance: Phase separation increases activity of the splicing factor SRSF9 to support progression of ovarian cancer by generating an oncogenic isoform of NUMB mRNA competitively with m6A modification, which provides promising therapeutic targets.

PPM1F regulates ovarian cancer progression by affecting the dephosphorylation of ITGB1

PPM1F has been shown to play diverse biological functions in the progression of multiple tumors. PPM1F controls the T788/T789 phosphorylation switch of ITGB1 and regulates integrin activity. However, the impacts of PPM1F and ITGB1 on ovarian cancer (OV) progression remain unclear. Whether there is such a regulatory relationship between PPM1F and ITGB1 in ovarian cancer has not been studied. Therefore, the purpose of this study is to elucidate the function and the mechanism of PPM1F in ovarian cancer. The expression level and the survival curve of PPM1F were analyzed by databases. Gain of function and loss of function were applied to explore the function of PPM1F in ovarian cancer. A tumor formation assay in nude mice showed that knockdown of PPM1F inhibited tumor formation. We tested the effect of PPM1F on ITGB1 dephosphorylation in ovarian cancer cells by co-immunoprecipitation and western blotting. Loss of function was applied to investigate the function of ITGB1 in ovarian cancer. ITGB1-mut overexpression promotes the progression of ovarian cancer. Rescue assays showed the promoting effect of ITGB1-wt on ovarian cancer is attenuated due to the dephosphorylation of ITGB1-wt by PPM1F. PPM1F and ITGB1 play an oncogene function in ovarian cancer. PPM1F regulates the phosphorylation of ITGB1, which affects the occurrence and development of ovarian cancer.