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

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 id...

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Veröffentlicht in:	eLife Jg. 10
Hauptverfasser:	Ho, Jessica SY, Di Tullio, Federico, Schwarz, Megan, Low, Diana, Incarnato, Danny, Gay, Florence, Tabaglio, Tommaso, Zhang, JingXian, Wollmann, Heike, Chen, Leilei, An, Omer, Chan, Tim Hon Man, Hall Hickman, Alexander, Zheng, Simin, Roudko, Vladimir, Chen, Sujun, Karz, Alcida, Ahmed, Musaddeque, He, Housheng Hansen, Greenbaum, Benjamin D, Oliviero, Salvatore, Serresi, Michela, Gargiulo, Gaetano, Mann, Karen M, Hernando, Eva, Mulholland, David, Marazzi, Ivan, Wee, Dave Keng Boon, Guccione, Ernesto
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	England eLife Sciences Publications Ltd 02.06.2021 eLife Sciences Publications, Ltd
Schlagworte:	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 genomics genetics splicing human circular RNA antisense oligonucleotides
ISSN:	2050-084X, 2050-084X
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Zusammenfassung:	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.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2050-084X 2050-084X
DOI:	10.7554/eLife.59654