REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer
Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer. / Svensson, Charlotte; Ceder, Jens; Iglesias Gato, Diego; Chuan, Yin Choy; Pang, See Tong; Bjartell, Anders; Martinez, Roxana Merino; Bott, Laura; Helczynski, Leszek; Ulmert, David; Wang, Yuzhuo; Niu, Yuanjie; Collins, Colin; Flores Morales, Amilcar.
I: Nucleic Acids Research, Bind 42, Nr. 2, 2014, s. 999-1015.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer
AU - Svensson, Charlotte
AU - Ceder, Jens
AU - Iglesias Gato, Diego
AU - Chuan, Yin Choy
AU - Pang, See Tong
AU - Bjartell, Anders
AU - Martinez, Roxana Merino
AU - Bott, Laura
AU - Helczynski, Leszek
AU - Ulmert, David
AU - Wang, Yuzhuo
AU - Niu, Yuanjie
AU - Collins, Colin
AU - Flores Morales, Amilcar
PY - 2014
Y1 - 2014
N2 - The androgen receptor (AR) is a key regulator of prostate tumorgenesis through actions that are not fully understood. We identified the repressor element (RE)-1 silencing transcription factor (REST) as a mediator of AR actions on gene repression. Chromatin immunoprecipitation showed that AR binds chromatin regions containing well-characterized cis-elements known to mediate REST transcriptional repression, while cell imaging studies confirmed that REST and AR closely co-localize in vivo. Androgen-induced gene repression also involves modulation of REST protein turnover through actions on the ubiquitin ligase β-TRCP. Androgen deprivation or AR blockage with inhibitor MDV3100 (Enzalutamide) leads to neuroendocrine (NE) differentiation, a phenomenon that is mimicked by REST inactivation. Gene expression profiling revealed that REST not only acts to repress neuronal genes but also genes involved in cell cycle progression, including Aurora Kinase A, that has previously been implicated in the growth of NE-like castration-resistant tumors. The analysis of prostate cancer tissue microarrays revealed that tumors with reduced expression of REST have higher probability of early recurrence, independently of their Gleason score. The demonstration that REST modulates AR actions in prostate epithelia and that REST expression is negatively correlated with disease recurrence after prostatectomy, invite a deeper characterization of its role in prostate carcinogenesis.
AB - The androgen receptor (AR) is a key regulator of prostate tumorgenesis through actions that are not fully understood. We identified the repressor element (RE)-1 silencing transcription factor (REST) as a mediator of AR actions on gene repression. Chromatin immunoprecipitation showed that AR binds chromatin regions containing well-characterized cis-elements known to mediate REST transcriptional repression, while cell imaging studies confirmed that REST and AR closely co-localize in vivo. Androgen-induced gene repression also involves modulation of REST protein turnover through actions on the ubiquitin ligase β-TRCP. Androgen deprivation or AR blockage with inhibitor MDV3100 (Enzalutamide) leads to neuroendocrine (NE) differentiation, a phenomenon that is mimicked by REST inactivation. Gene expression profiling revealed that REST not only acts to repress neuronal genes but also genes involved in cell cycle progression, including Aurora Kinase A, that has previously been implicated in the growth of NE-like castration-resistant tumors. The analysis of prostate cancer tissue microarrays revealed that tumors with reduced expression of REST have higher probability of early recurrence, independently of their Gleason score. The demonstration that REST modulates AR actions in prostate epithelia and that REST expression is negatively correlated with disease recurrence after prostatectomy, invite a deeper characterization of its role in prostate carcinogenesis.
U2 - 10.1093/nar/gkt921
DO - 10.1093/nar/gkt921
M3 - Journal article
C2 - 24163104
VL - 42
SP - 999
EP - 1015
JO - Nucleic Acids Research
JF - Nucleic Acids Research
SN - 0305-1048
IS - 2
ER -
ID: 68110718