HNRNPM controls circRNA biogenesis and splicing fidelity to sustain prostate cancer cell fitness

Cancer cells are differentially dependent on the splicing machinery compared to normal untransformed cells. The splicing machinery thus represents a potential therapeutic target in cancer. To identify splicing factors important for prostate cancer cell (PCa) cell growth, we performed a parallel pooled shRNA screen on in vitro passaged cells and in vivo xenografted PCa tumor lines. Our screen revealed HNRNPM as a potential regulator of PCa cell growth. RNA- and eCLIP-sequencing data suggest that HNRNPM is bound to transcripts of key homeostatic genes and that loss of HNRNPM binding in a subset of these genes results in aberrant exon inclusion and exon back-splicing events in target transcripts. In both linear and circular mis-spliced transcripts, HNRNPM appears to preferentially bind to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM dependent linear splicing events using splice-switching antisense oligonucleotides (SSOs) was sufficient to inhibit cell growth in HNRNPM expressing cells. This suggests that prostate cancer cell dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Taken together, our data reveal a role for HNRNPM in supporting prostate cancer cell fitness, and also as a potential therapeutic target in PCa.