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Title: HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness
Authors: Ho, Jessica S. Y.
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
Hickman, Alexander Hall
Zheng, Simin
Roudko, Vladimir
Chen, Sujun
Karz, Alcida
Ahmed, Musaddeque
He, Hansen Housheng
Greenbaum, Benjamin D.
Oliviero, Salvatore
Serresi, Michela
Gargiulo, Gaetano
Mann, Karen M.
Hernando, Eva
Mulholland, David
Marazzi, Ivan
Wee, Dave Keng Boon
Guccione, Ernesto
Keywords: Science::Biological sciences
Issue Date: 2021
Source: Ho, J. S. Y., Di Tullio, F., Schwarz, M., Low, D., Incarnato, D., Gay, F., Tabaglio, T., Zhang, J., Wollmann, H., Chen, L., An, O., Chan, T. H. M., Hickman, A. H., Zheng, S., Roudko, V., Chen, S., Karz, A., Ahmed, M., He, H. H., ...Guccione, E. (2021). HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness. ELife, 10, e59654-.
Project: P30 CA196521
Journal: eLife
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 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.
ISSN: 2050-084X
DOI: 10.7554/eLife.59654
Schools: School of Biological Sciences 
Rights: © 2021 Ho et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
Fulltext Permission: open
Fulltext Availability: With Fulltext
Appears in Collections:SBS Journal Articles

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