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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Published in:eLife Vol. 10
Main Authors: 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
Language:English
Published: England eLife Sciences Publications Ltd 02.06.2021
eLife Sciences Publications, Ltd
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.59654