PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression

PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression

Genome Medicine

10.1186/s13073-024-01328-1

http://dx.doi.org/10.1186/s13073-024-01328-1

Yi Fei Lee, Cheryl Zi Jin Phua, Ju Yuan, Bin Zhang, May Yin Lee, Srinivasaraghavan Kannan, Yui Hei Jasper Chiu, Casslynn Wei Qian Koh, Choon Kong Yap, Edwin Kok Hao Lim, Jianbin Chen, Yuhua Lim, Jane Jia Hui Lee, Anders Jacobsen Skanderup, Zhenxun Wang, Weiwei Zhai, Nguan Soon Tan, Chandra S. Verma, Yvonne Tay, Daniel Shao Weng Tan, Wai Leong Tam

21 July 2024

Lee, Y. F., Phua, C. Z. J., Yuan, J., Zhang, B., Lee, M. Y., Kannan, S., Chiu, Y. H. J., Koh, C. W. Q., Yap, C. K., Lim, E. K. H., Chen, J., Lim, Y., Lee, J. J. H., Skanderup, A. J., Wang, Z., Zhai, W., Tan, N. S., Verma, C. S., Tay, Y., … Tam, W. L. (2024). PARP4 interacts with hnRNPM to regulate splicing during lung cancer progression. Genome Medicine, 16(1). https://doi.org/10.1186/s13073-024-01328-1

Background: The identification of cancer driver genes from sequencing data has been crucial in deepening our understanding of tumor biology and expanding targeted therapy options. However, apart from the most commonly altered genes, the mechanisms underlying the contribution of other mutations to cancer acquisition remain understudied. Leveraging on our whole-exome sequencing of the largest Asian lung adenocarcinoma (LUAD) cohort (n = 302), we now functionally assess the mechanistic role of a novel driver, PARP4. Methods: In vitro and in vivo tumorigenicity assays were used to study the functional effects of PARP4 loss and mutation in multiple lung cancer cell lines. Interactomics analysis by quantitative mass spectrometry was conducted to identify PARP4’s interaction partners. Transcriptomic data from cell lines and patient tumors were used to investigate splicing alterations. Results: PARP4 depletion or mutation (I1039T) promotes the tumorigenicity of KRAS- or EGFR-driven lung cancer cells. Disruption of the vault complex, with which PARP4 is commonly associated, did not alter tumorigenicity, indicating that PARP4’s tumor suppressive activity is mediated independently. The splicing regulator hnRNPM is a potentially novel PARP4 interaction partner, the loss of which likewise promotes tumor formation. hnRNPM loss results in splicing perturbations, with a propensity for dysregulated intronic splicing that was similarly observed in PARP4 knockdown cells and in LUAD cohort patients with PARP4 copy number loss. Conclusions: PARP4 is a novel modulator of lung adenocarcinoma, where its tumor suppressive activity is mediated not through the vault complex—unlike conventionally thought, but in association with its novel interaction partner hnRNPM, thus suggesting a role for splicing dysregulation in LUAD tumorigenesis.

Attribution 4.0 International (CC BY 4.0)

This research / project is supported by the National Medical Research Council, Singapore - N/A
Grant Reference no. : NMRC/OFLCG/002–2018, NMRC/OFIRG/0064/2017, OFIRG19nov-0106, OFIRG21nov-0068

This research / project is supported by the National Research Foundation, Singapore - N/A
Grant Reference no. : NRF-NRFF2015-04, NRF-NRFI08-2022

This research / project is supported by the Ministry of Education, Singapore - Research Centers of Excellence initiative
Grant Reference no. :

This research is supported by core funding from: Agency for Science, Technology and Research, Singapore
Grant Reference no. :

©The Author(s) 2024.Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visithttp://creativecommons.org/licenses/by/4.0/.The Creative Commons Public Domain Dedication waiver (http://creativecom-mons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data

https://oar.a-star.edu.sg/communities-collections/articles/20841

1756-994X

Genome Institute of Singapore

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