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

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Item Type:Article
Title:HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness
Creators Name:Ho, J.S. and Di Tullio, F. and Schwarz, M. and Low, D. and Incarnato, D. and Gay, F. and Tabaglio, T. and Zhang, J.X. and Wollmann, H. and Chen, L. and An, O. and Chan, T.H.M. and Hall Hickman, A. and Zheng, S. and Roudko, V. and Chen, S. and Karz, A. and Ahmed, M. and He, H.H. and Greenbaum, B.D. and Oliviero, S. and Serresi, M. and Gargiulo, G. and Mann, K.M. and Hernando, E. and Mulholland, D. and Marazzi, I. and Wee, D.K.B. and Guccione, E.
Abstract: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 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 back-splicing 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 (SSOs) 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.
Keywords:hnRNPM, Prostate Cancer, Splicing, Circular RNA, Chromatin, Histone Methylation, EED, H3K27me3, Animals, Mice
Publisher:eLife Sciences Publications
Page Range:e59654
Date:2 June 2021
Official Publication:https://doi.org/10.7554/eLife.59654
PubMed:View item in PubMed
Related to:
https://edoc.mdc-berlin.de/19070/Preprint version

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