Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

Munkley, J.; Ling, L.; Krishnan, S. R. G.; Hysenaj, G.; Scott, E.; Oo, H. Z.; Maia, T.; Cheung, K.; Ehrmann, I.; Livermore, K.; Zielinska, H.; Thompson, O.; Knight, B.; McCullagh, P.; McGrath, J.; Crundwell, M.; Harries, L. W.; Daugaard, M.; Cockell, S.; Barbosa-Morais, N. L.; Oltean, S.; Elliott, D. J.

doi:10.1101/629618

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bioRxiv · 10.1101/629618

Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer

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Abstract

Prostate is the most frequent cancer in men. Prostate cancer progression is driven by androgen steroid hormones, and delayed by androgen deprivation therapy (ADT). Androgens control transcription by stimulating androgen receptor (AR) activity, yet also control pre-mRNA splicing through less clear mechanisms. Here we find androgens regulate splicing through AR-mediated transcriptional control of the epithelial-specific splicing regulator ESRP2. Both ESRP2 and its close paralog ESRP1 are highly expressed in primary prostate cancer. Androgen stimulation induces splicing switches in many endogenous ESRP2-controlled mRNA isoforms, including a key splicing switch in the metastatic regulator FLNB which is associated with disease relapse. ESRP2 expression in clinical prostate cancer is repressed by ADT, which may thus inadvertently dampen epithelial splice programmes. Supporting this, FLNB splicing was reciprocally switched by the AR antagonist bicalutamide (Casodex(R)). Our data reveal a new mechanism of splicing control in prostate cancer with important implications for metastatic disease progression.\n\nKey pointsO_LITranscriptional regulation of ESRP2 by the androgen receptor controls splice isoform patterns in prostate cancer cells.\nC_LIO_LISplicing switches regulated by the androgen-ESRP2 axis include a splice isoform in the FLNB gene that is a known metastatic driver.\nC_LIO_LIBoth ESRP1 and ESRP2 are highly expressed in prostate cancer tissue.\nC_LIO_LIEctopic expression of ESRP1 and 2 inhibits prostate cancer cell growth.\nC_LIO_LIBy repressing ESRP2 expression androgen deprivation therapy (ADT) may dampen epithelial splicing programmes to inadvertently prime disease progression towards metastasis.\nC_LI

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Munkley, J., Ling, L., Krishnan, S. R. G., Hysenaj, G., Scott, E., Oo, H. Z., Maia, T., Cheung, K., Ehrmann, I., Livermore, K., Zielinska, H., Thompson, O., Knight, B., McCullagh, P., McGrath, J., Crundwell, M., Harries, L. W., Daugaard, M., Cockell, S., Barbosa-Morais, N. L., Oltean, S., Elliott, D. J.. 2019-05-08. Androgen-regulated transcription of ESRP2 drives alternative splicing patterns in prostate cancer. https://doi.org/10.1101/629618

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