Affiliations
- 1Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore.
- 2School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
- 3Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
- 4Computational Bioscience Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
- 5Computer Science Program, Computer, Electrical and Mathematical Sciences and Engineering Division, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia.
- 6Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, Matrix, Singapore, 138671, Singapore.
- 7Centre for Vision Research, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
- 8Key Laboratory of Zoological Systematics and Evolution, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
- 9Center for Excellence in Animal Evolution and Genetics, Chinese Academy of Sciences, Kunming, China.
- 10Lee Kong Chian School of Medicine, Nanyang Technological University, 11 Mandalay Road, Singapore, 308232, Singapore.
- 11Department of Biological Sciences, National University of Singapore, 16 Science Drive 4, Singapore, 117558, Singapore.
- 12NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
- 13Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore, 117597, Singapore.
- 14Division of Medical Oncology, National Cancer Centre Singapore, 30 Hospital Boulevard, Singapore, 168583, Singapore.
- 15Genome Institute of Singapore (GIS), Agency for Science, Technology and Research (A*STAR), 60 Biopolis Street, Genome, Singapore, 138672, Singapore. tamwl@gis.a-star.edu.sg.
- 16Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore. tamwl@gis.a-star.edu.sg.
- 17NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore. tamwl@gis.a-star.edu.sg.
- 18Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, 8 Medical Drive, Singapore, 117597, Singapore. tamwl@gis.a-star.edu.sg.
Abstract
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.
- PMID: 39034402 PMCID: PMC11265163 DOI: 10.1186/s13073-024-01328-1