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

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.

<i>Artesunate</i> Suppresses the Growth of Prostatic Cancer Cells through Inhibiting Androgen Receptor

“…19) Increasing evidences pointed that AR was a critical mediator for anti-prostate cancer. [20][21][22] In view of this, researchers tended to explore agents to antagonize AR as improved therapeutic methods for prostatic cancer. A natural prenylflavonoid, also known as icaritin (ICT), inhibited AR-regulated genes in AR-positive prostate cancer cells via AR-depended pathways.…”

The Role of Epigenetics and Long Noncoding RNA MIAT in Neuroendocrine Prostate Cancer

“…REST is part of the KDM1A-coREST-REST (Lysine-specific histone demethylase 1A-REST Corepressor 1-RE1-silencing transcription factor) histone modifying complex which is bound by HOTAIR, a long intergenic ncRNA that coordinates histone H3 lysine 27 methylation and lysine 4 demethylation [54]. Given that REST is commonly inactivated in NEPC and is responsible for repressing neuronal genes [55], aberrant silencing of this gene could trigger neuronal differentiation programs in trans-differentiating cells [56].…”

“…REST is part of the KDM1A-coREST-REST (Lysine-specific histone demethylase 1A-REST Corepressor 1-RE1-silencing transcription factor) histone modifying complex which is bound by HOTAIR, a long intergenic ncRNA that coordinates histone H3 lysine 27 methylation and lysine 4 demethylation [54]. Given that REST is commonly inactivated in NEPC and is responsible for repressing neuronal genes [55], aberrant silencing of this gene could trigger neuronal differentiation programs in trans-differentiating cells [56].Notably, epigenetic modifications are known to precede genetic alterations in human neoplasms [57]. Therefore, we believe that the ENI plays a significant role in the initiating stages of NEPC trans-differentiation via epigenetic modification of downstream gene targets.…”

A Prominent Couple

“…This concept assumes evolution of NED from adenocarcinoma cells into NE cells, underpinned by the detection of epithelial characteristics in NE cells such as expression of CK8, CK18, and AMACR [84,95,96]. Several signaling mediators have been implicated in NED including neuropeptides (bombesin/gastrin-releasing peptide, calcitonin, serotonin, and vasoactive intestinal peptide) [97], cytokines (IL-6, IL-1β, IL-8) [98][99][100], ionizing irradiation [101], and stimuli elevating intra-cellular cAMP (such as forskolin) [102]. LNCaP cells cultured with cAMP or charcoal-stripped fetal bovine serum acquired a NE phenotype [103,104].…”

“…IL-6 triggered REST repression and STAT3-induced NED in LNCaP cells [106][107][108]. Neuropeptides and IL-8 activated the nonreceptor tyrosine kinases ETK, Src and FAK resulting in androgenindependent AR activation [100,109]. In a transgenic adenocarcinoma of the mouse prostate (TRAMP) model, cooperativity between the NE-specific forkhead transcription factor FoxA2 and the hypoxia-induced transcription factor HIF1α induced target genes that were required for a NE phenotype in PCa [110].…”