Affiliations
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. csihj@nus.edu.sg.
2Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
3Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117549, Singapore.
4Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117596, Singapore.
5NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore.
6Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. polly_chen@nus.edu.sg.
7NUS Centre for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore. polly_chen@nus.edu.sg.
8Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117594, Singapore. polly_chen@nus.edu.sg.
Abstract
The dynamic regulation of alternative splicing requires coordinated participation of multiple RNA binding proteins (RBPs). Aberrant splicing caused by dysregulation of splicing regulatory RBPs is implicated in numerous cancers. Here, we reveal a frequently overexpressed cancer-associated protein, DAP3, as a splicing regulatory RBP in cancer. Mechanistically, DAP3 coordinates splicing regulatory networks, not only via mediating the formation of ribonucleoprotein complexes to induce substrate-specific splicing changes, but also via modulating splicing of numerous splicing factors to cause indirect effect on splicing. A pan-cancer analysis of alternative splicing across 33 TCGA cancer types identified DAP3-modulated mis-splicing events in multiple cancers, and some of which predict poor prognosis. Functional investigation of non-productive splicing of WSB1 provides evidence for establishing a causal relationship between DAP3-modulated mis-splicing and tumorigenesis. Together, our work provides critical mechanistic insights into the splicing regulatory roles of DAP3 in cancer development.
© 2022. The Author(s).
PMID: 35379802 PMCID: PMC8980049 DOI: 10.1038/s41467-022-29400-7