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.
Nature communications. 2017 Jun 30*** epublish ***
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
Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, District Of Columbia 20037, USA., Department of Microbiology, Immunology and Tropical Medicine, School of Medicine and Health Sciences, The George Washington University, Washington, District Of Columbia 20037, USA., Department of Urology, School of Medicine and Health Sciences, The George Washington University, Washington, District Of Columbia 20037, USA., Duke Cancer Institute and Department of Medicine, Duke University Medical Center, Durham, North Carolina 27710, USA., Department of Clinical Pharmacology, University of Oxford, Oxford OX3 7BN, UK., Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii 96813, USA., Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892, USA., Department of Biochemistry &Molecular Biology, The University of Texas Medical Branch at Galveston, Galveston, Texas 77555, USA.