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...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Other Authors: | |
| Format: | Journal Article |
| Language: | English |
| Published: |
2022
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| Subjects: | |
| Online Access: | https://hdl.handle.net/10356/160757 |
| _version_ | 1811692454214107136 |
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| author | 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 |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences 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 |
| author_sort | Ho, Jessica S. Y. |
| collection | NTU |
| description | 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. |
| first_indexed | 2024-10-01T06:36:02Z |
| format | Journal Article |
| id | ntu-10356/160757 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T06:36:02Z |
| publishDate | 2022 |
| record_format | dspace |
| spelling | ntu-10356/1607572023-02-28T17:12:07Z HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness 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 School of Biological Sciences Science::Biological sciences Circular Ribonucleic Acid Animal Experiment 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. Published version EG and DW acknowledge support from NMRC/OFIRG/0032/2017 and NRF-CRP17-2017-06. Research reported in this publication was supported in part by National Cancer Institute of the NIH (R01CA249204) and ISMMS seed fund to EG and Melanoma Research Alliance MRA Team Science Award to EH and EG. SZ was supported by the Lee Kuan Yew Endowment Fund Postdoctoral Fellowship. The authors gratefully acknowledge the use of the services and facilities of the Tisch Cancer Institute supported by the NCI Cancer Center Support Grant (P30 CA196521). MS was supported by a NCI training grant (T32CA078207). GG lab was supported by the MDC, the Helmholtz Association, and the ERC. DM was supported by NCI-R01CA197910. 2022-08-02T05:38:32Z 2022-08-02T05:38:32Z 2021 Journal Article 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-. https://dx.doi.org/10.7554/eLife.59654 2050-084X https://hdl.handle.net/10356/160757 10.7554/eLife.59654 34075878 2-s2.0-85109024973 10 e59654 en P30 CA196521 eLife © 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. application/pdf |
| spellingShingle | Science::Biological sciences Circular Ribonucleic Acid Animal Experiment 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 HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness |
| title | HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness |
| title_full | HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness |
| title_fullStr | HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness |
| title_full_unstemmed | HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness |
| title_short | HNRNPM controls circRNA biogenesis and splicing fidelity to sustain cancer cell fitness |
| title_sort | hnrnpm controls circrna biogenesis and splicing fidelity to sustain cancer cell fitness |
| topic | Science::Biological sciences Circular Ribonucleic Acid Animal Experiment |
| url | https://hdl.handle.net/10356/160757 |
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