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Volume 25, Issue 3 (May 2023) 25, 296–308; 10.4103/aja202263

Investigation of androgen receptor-dependent alternative splicing has identified a unique subtype of lethal prostate cancer

Sean Seltzer1, Paresa N Giannopoulos1, Tarek A Bismar2, Mark Trifiro1,3, Miltiadis Paliouras1,3,4

1 Lady Davis Institute for Medical Research, Segal Cancer Centre - Jewish General Hospital, Montreal, QC H3T 1E2, Canada
    2 Cumming School of Medicine, Department of Pathology and Laboratory Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada
    3 Department of Medicine, Division of Experimental Medicine, McGill University, Montreal, QC H4A 3J1, Canada
    4 Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada

Correspondence: Dr. M Paliouras (miltiadis.paliouras@mcgill.ca)



A complete proteomics study characterizing active androgen receptor (AR) complexes in prostate cancer (PCa) cells identified a diversity of protein interactors with tumorigenic annotations, including known RNA splicing factors. Thus, we chose to further investigate the functional role of AR-mediated alternative RNA splicing in PCa disease progression. We selected two AR-interacting RNA splicing factors, Src associated in mitosis of 68 kDa (SAM68) and DEAD (Asp-Glu-Ala-Asp) box helicase 5 (DDX5) to examine their associative roles in AR-dependent alternative RNA splicing. To assess the true physiological role of AR in alternative RNA splicing, we assessed splicing profiles of LNCaP PCa cells using exon microarrays and correlated the results to PCa clinical datasets. As a result, we were able to highlight alternative splicing events of clinical significance. Initial use of exon-mini gene cassettes illustrated hormone-dependent AR-mediated exon-inclusion splicing events with SAM68 or exon-exclusion splicing events with DDX5 overexpression. The physiological significance in PCa was investigated through the application of clinical exon array analysis, where we identified exon-gene sets that were able to delineate aggressive disease progression profiles and predict patient disease-free outcomes independently of pathological clinical criteria. Using a clinical dataset with patients categorized as prostate cancer-specific death (PCSD), these exon gene sets further identified a select group of patients with extremely poor disease-free outcomes. Overall, these results strongly suggest a nonclassical role of AR in mediating robust alternative RNA splicing in PCa. Moreover, AR-mediated alternative spicing contributes to aggressive PCa progression, where we identified a new subtype of lethal PCa defined by AR-dependent alternative splicing.
    Keywords: alternative RNA splicing; androgen receptor; exon-gene sets; lethal prostate cancer subtype; prostate cancer

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Asian Journal of Andrology CN 31-1795/R ISSN 1008-682X  Copyright © 2023  Shanghai Materia Medica, Chinese Academy of Sciences.  All rights reserved.