eLife (Jun 2021)
HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness
- Jessica SY Ho,
- Federico Di Tullio,
- Megan Schwarz,
- Diana Low,
- Danny Incarnato,
- Florence Gay,
- Tommaso Tabaglio,
- JingXian Zhang,
- Heike Wollmann,
- Leilei Chen,
- Omer An,
- Tim Hon Man Chan,
- Alexander Hall Hickman,
- Simin Zheng,
- Vladimir Roudko,
- Sujun Chen,
- Alcida Karz,
- Musaddeque Ahmed,
- Housheng Hansen He,
- Benjamin D Greenbaum,
- Salvatore Oliviero,
- Michela Serresi,
- Gaetano Gargiulo,
- Karen M Mann,
- Eva Hernando,
- David Mulholland,
- Ivan Marazzi,
- Dave Keng Boon Wee,
- Ernesto Guccione
Affiliations
- Jessica SY Ho
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, United States
- Federico Di Tullio
- Center for Therapeutics Discovery, department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
- Megan Schwarz
- Center for Therapeutics Discovery, department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
- Diana Low
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Danny Incarnato
- IIGM (Italian Institute for Genomic Medicine), Torino, Italy; Dipartimento di Scienze della Vita e Biologia dei Sistemi Università di Torino, Torino, Italy; Department of Molecular Genetics, Groningen Biomolecular Sciences and Biotechnology Institute (GBB), University of Groningen, Groningen, Netherlands
- Florence Gay
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Tommaso Tabaglio
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- JingXian Zhang
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Heike Wollmann
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Leilei Chen
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore; Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Omer An
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Tim Hon Man Chan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
- Alexander Hall Hickman
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Simin Zheng
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, United States; NTU Institute of Structural Biology, Nanyang Technological University, Singapore, Singapore
- Vladimir Roudko
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
- Sujun Chen
- Department of Medical Biophysics, University of Toronto, Toronto, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Canada; Ontario Institute for Cancer Research, Toronto, Canada
- Alcida Karz
- Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, United States; Department of Pathology, New York University Langone Medical Center, New York, United States
- Musaddeque Ahmed
- Princess Margaret Cancer Center, University Health Network, Toronto, Canada
- Housheng Hansen He
- Department of Medical Biophysics, University of Toronto, Toronto, Canada; Princess Margaret Cancer Center, University Health Network, Toronto, Canada
- Benjamin D Greenbaum
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Medicine, Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, United States
- Salvatore Oliviero
- ORCiD
- IIGM (Italian Institute for Genomic Medicine), Torino, Italy; Dipartimento di Scienze della Vita e Biologia dei Sistemi Università di Torino, Torino, Italy
- Michela Serresi
- Max Delbruck Center for Molecular Medicine, Berlin-Buch, Germany
- Gaetano Gargiulo
- Max Delbruck Center for Molecular Medicine, Berlin-Buch, Germany
- Karen M Mann
- Department of Molecular Oncology, Moffitt Cancer Center, Tampa, United States
- Eva Hernando
- Interdisciplinary Melanoma Cooperative Group, New York University Langone Medical Center, New York, United States; Department of Pathology, New York University Langone Medical Center, New York, United States
- David Mulholland
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
- Ivan Marazzi
- Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, United States
- Dave Keng Boon Wee
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore
- Ernesto Guccione
- ORCiD
- Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology and Research (A*STAR), Singapore, Singapore; Center for Therapeutics Discovery, department of Oncological Sciences and Pharmacological Sciences, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, United States; Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, United States
- DOI
- https://doi.org/10.7554/eLife.59654
- Journal volume & issue
-
Vol. 10
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.
Keywords