Journal Article

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

Di Tullio, Federico, Mann, Karen M, Hernando, Eva, He, Housheng Hansen, Schwarz, Megan, Hall Hickman, Alexander, Tabaglio, Tommaso, Ho, Jessica SY, Zheng, Simin, Ahmed, Musaddeque, Serresi, Michela, Mulholland, David, Wollmann, Heike, Gargiulo, Gaetano, Low, Diana, Karz, Alcida, Marazzi, Ivan, Zhang, JingXian, Guccione, Ernesto, Chan, Tim Hon Man, Oliviero, Salvatore, Chen, Leilei, Incarnato, Danny, Roudko, Vladimir, Gay, Florence, Chen, Sujun, Wee, Dave Keng Boon, An, Omer, Greenbaum, Benjamin D

2021

Overview

High spliceosome activity is a dependency for cancer cells, making them more vulnerable to perturbation of the splicing machinery compared to normal cells. To identify splicing factors important for prostate cancer (PCa) fitness, we performed pooled shRNA screens in vitro and in vivo. Our screens identified heterogeneous nuclear ribonucleoprotein M (HNRNPM) as a regulator of PCa cell growth. RNA- and eCLIP-sequencing identified HNRNPM binding to transcripts of key homeostatic genes. HNRNPM binding to its targets prevents aberrant exon inclusion and backsplicing events. In both linear and circular mis-spliced transcripts, HNRNPM preferentially binds to GU-rich elements in long flanking proximal introns. Mimicry of HNRNPM-dependent linear-splicing events using splice-switching-antisense-oligonucleotides was sufficient to inhibit PCa cell growth. This suggests that PCa dependence on HNRNPM is likely a result of mis-splicing of key homeostatic coding and non-coding genes. Our results have further been confirmed in other solid tumors. Taken together, our data reveal a role for HNRNPM in supporting cancer cell fitness. Inhibition of HNRNPM activity is therefore a potential therapeutic strategy in suppressing growth of PCa and other solid tumors.

• Publisher: eLife Sciences Publications Ltd,eLife Sciences Publications, Ltd
• Subject: Adenocarcinoma - genetics / Adenocarcinoma - metabolism / Adenocarcinoma - pathology / Animals / Antisense oligonucleotides / Biosynthesis / Cell growth / Cell Proliferation / circular RNA / Fitness / Gene expression / Gene Expression Regulation, Neoplastic / Genetics and Genomics / Genomes / Hep G2 Cells / Heterogeneous-Nuclear Ribonucleoprotein Group M - genetics / Heterogeneous-Nuclear Ribonucleoprotein Group M - metabolism / Humans / Introns / Male / Mice / Mice, SCID / Mimicry / Mutation / Oligonucleotides / PC-3 Cells / Prostate cancer / Prostatic Neoplasms - genetics / Prostatic Neoplasms - metabolism / Prostatic Neoplasms - pathology / RNA Splicing / RNA, Circular - biosynthesis / RNA, Circular - genetics / Solid tumors / splicing / Splicing factors / Tumor Burden / Tumor Cells, Cultured / Tumors