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 and Norman H. Lee ()
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Bi-Dar Wang: School of Medicine and Health Sciences, The George Washington University
Kristin Ceniccola: School of Medicine and Health Sciences, The George Washington University
SuJin Hwang: Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University
Ramez Andrawis: School of Medicine and Health Sciences, The George Washington University
Anelia Horvath: School of Medicine and Health Sciences, The George Washington University
Jennifer A. Freedman: Duke University Medical Center
Jacqueline Olender: School of Medicine and Health Sciences, The George Washington University
Stefan Knapp: University of Oxford
Travers Ching: Cancer Epidemiology Program, University of Hawaii Cancer Center
Lana Garmire: Cancer Epidemiology Program, University of Hawaii Cancer Center
Vyomesh Patel: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health
Mariano A. Garcia-Blanco: The University of Texas Medical Branch at Galveston
Steven R. Patierno: Duke University Medical Center
Norman H. Lee: School of Medicine and Health Sciences, The George Washington University

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms15921

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