Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer

Bi Dar Wang, Kristin Ceniccola, Sujin Hwang, Ramez Andrawis, Anelia Horvath, Jennifer A. Freedman, Jacqueline Olender, Stefan Knapp, Travers Ching, Lana Garmire, Vyomesh Patel, Mariano A. Garcia-Blanco, Steven R. Patierno, Norman H. Lee

Research output: Contribution to journalArticle

33 Scopus citations

Abstract

Clinical challenges exist in reducing prostate cancer (PCa) disparities. The RNA splicing landscape of PCa across racial populations has not been fully explored as a potential molecular mechanism contributing to race-related tumour aggressiveness. Here, we identify novel genome-wide, race-specific RNA splicing events as critical drivers of PCa aggressiveness and therapeutic resistance in African American (AA) men. AA-enriched splice variants of PIK3CD, FGFR3, TSC2 and RASGRP2 contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, PIK3CD-S, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity in vitro and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High PIK3CD-S expression in PCa specimens associates with poor survival. These results highlight the potential of RNA splice variants to serve as novel biomarkers and molecular targets for developmental therapeutics in aggressive PCa.

Original languageEnglish (US)
Article number15921
JournalNature communications
Volume8
DOIs
StatePublished - Jun 30 2017

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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    Wang, B. D., Ceniccola, K., Hwang, S., Andrawis, R., Horvath, A., Freedman, J. A., Olender, J., Knapp, S., Ching, T., Garmire, L., Patel, V., Garcia-Blanco, M. A., Patierno, S. R., & Lee, N. H. (2017). Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer. Nature communications, 8, [15921]. https://doi.org/10.1038/ncomms15921