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Mechanisms of the androgen receptor splicing in prostate cancer cells

Oncogene volume 33, pages 3140–3150 (2014)Cite this article

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Abstract

Prostate tumors develop resistance to androgen deprivation therapy (ADT) by multiple mechanisms, one of which is to express constitutively active androgen receptor (AR) splice variants lacking the ligand-binding domain. AR splice variant 7 (AR-V7, also termed AR3) is the most abundantly expressed variant that drives prostate tumor progression under ADT conditions. However, the molecular mechanism by which AR-V7 is generated remains unclear. In this manuscript, we demonstrated that RNA splicing of AR-V7 in response to ADT was closely associated with AR gene transcription initiation and elongation rates. Enhanced AR gene transcription by ADT provides a prerequisite condition that further increases the interactions between AR pre-mRNA and splicing factors. Under ADT conditions, recruitment of several RNA splicing factors to the 3′ splicing site for AR-V7 was increased. We identified two RNA splicing enhancers and their binding proteins (U2AF65 and ASF/SF2) that had critical roles in splicing AR pre-mRNA into AR-V7. These data indicate that ADT-induced AR gene transcription rate and splicing factor recruitment to AR pre-mRNA contribute to the enhanced AR-V7 levels in prostate cancer cells.

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Acknowledgements

This study was supported by Pacific Northwest Prostate Cancer SPORE, National Cancer Institute (P50CA097186; XD and SRP); Prostate Cancer Canada (RS2013-58; to XD) and Canadian Institute of Health Research (MOP-97934; XD); Department of Defence plus Veterans Administration Grants (SRP), NIH P01 CA163227 (SRP) and Prostate Cancer Foundation (SRP).

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Authors and Affiliations

  1. Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada

    L L Liu, N Xie & X Dong

  2. Department of Medicine, University of Washington School of Medicine and VAPSHCS-GRECC, Seattle, WA, USA

    S Sun & S Plymate

  3. Fred Hutchinson Cancer Research Center, Seattle, WA, USA

    E Mostaghel

  4. Department of Obstetrics and Gynaecology, University of Toronto, Toronto, Ontario, Canada

    X Dong

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  1. L L Liu
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Correspondence to S Plymate or X Dong.

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Liu, L., Xie, N., Sun, S. et al. Mechanisms of the androgen receptor splicing in prostate cancer cells. Oncogene 33, 3140–3150 (2014). https://doi.org/10.1038/onc.2013.284

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