Alternative splicing promotes tumour aggressiveness and drug resistance in African American prostate cancer
説明
<jats:title>Abstract</jats:title><jats:p>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 <jats:italic>PIK3CD</jats:italic>, <jats:italic>FGFR3</jats:italic>, <jats:italic>TSC2</jats:italic> and <jats:italic>RASGRP2</jats:italic> contribute to greater oncogenic potential compared with corresponding European American (EA)-expressing variants. Ectopic overexpression of the newly cloned AA-enriched variant, <jats:italic>PIK3CD-S</jats:italic>, in EA PCa cell lines enhances AKT/mTOR signalling and increases proliferative and invasive capacity <jats:italic>in vitro</jats:italic> and confers resistance to selective PI3Kδ inhibitor, CAL-101 (idelalisib), in mouse xenograft models. High <jats:italic>PIK3CD-S</jats:italic> 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.</jats:p>
収録刊行物
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- Nature Communications
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Nature Communications 8 (1), 2017-06-30
Springer Science and Business Media LLC
