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REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer.

Svensson, Charlotte; Ceder, Jens LU ; Iglesias-Gato, Diego; Chuan, Yin-Choy; Pang, See Tong; Bjartell, Anders LU ; Martinez, Roxana Merino; Bott, Laura; Helczynski, Leszek LU and Ulmert, David LU , et al. (2014) In Nucleic Acids Research 42(2). p.999-1015
Abstract
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... (More)
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. (Less)
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Nucleic Acids Research
volume
42
issue
2
pages
999 - 1015
publisher
Oxford University Press
external identifiers
  • pmid:24163104
  • wos:000331138100032
  • scopus:84893296911
ISSN
1362-4962
DOI
10.1093/nar/gkt921
language
English
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yes
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b38baf0f-98f1-479f-8f60-1b95c31fda09 (old id 4142947)
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http://www.ncbi.nlm.nih.gov/pubmed/24163104?dopt=Abstract
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2013-11-04 21:50:45
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@article{b38baf0f-98f1-479f-8f60-1b95c31fda09,
  abstract     = {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.},
  author       = {Svensson, Charlotte and Ceder, Jens and Iglesias-Gato, Diego and Chuan, Yin-Choy and Pang, See Tong and Bjartell, Anders and Martinez, Roxana Merino and Bott, Laura and Helczynski, Leszek and Ulmert, David and Wang, Yuzhuo and Niu, Yuanjie and Collins, Colin and Flores-Morales, Amilcar},
  issn         = {1362-4962},
  language     = {eng},
  number       = {2},
  pages        = {999--1015},
  publisher    = {Oxford University Press},
  series       = {Nucleic Acids Research},
  title        = {REST mediates androgen receptor actions on gene repression and predicts early recurrence of prostate cancer.},
  url          = {http://dx.doi.org/10.1093/nar/gkt921},
  volume       = {42},
  year         = {2014},
}