title: 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.
authors.affiliation: Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark, Division of Urological Cancers, Department of Clinical Sciences, Skåne University Hospital, Lund University, 20502 Malmö, Sweden, Department of Urology, Chang Gung Memorial Hospital, Tao-Yuan 33305, Taiwan, R.O.C., Department of Epidemiology, Karolinska Institutet, 171 77 Stockholm, Sweden, Department of Cell and Molecular Biology, Karolinska Institute, 171 77 Stockholm, Sweden, Regional Laboratories Region Skåne, Clinical Pathology, 205 80 Malmö, Sweden, Department of Surgery (Urology), Memorial Sloan-Kettering Cancer Center, New York, NY 100 65, USA, Vancouver Prostate Centre and The Department of Urologic Sciences, University of British Columbia, Vancouver, BC Canada V6H 3Z6 and Tianjin Institute of Urology, Tianjin Medical University, Tianjin 300 211, China.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Svensson
authors.forename: Jens
authors.initials: J
authors.lastname: Ceder
authors.forename: Diego
authors.initials: D
authors.lastname: Iglesias-Gato
authors.forename: Yin-Choy
authors.initials: YC
authors.lastname: Chuan
authors.forename: See Tong
authors.initials: ST
authors.lastname: Pang
authors.forename: Anders
authors.initials: A
authors.lastname: Bjartell
authors.forename: Roxana Merino
authors.initials: RM
authors.lastname: Martinez
authors.forename: Laura
authors.initials: L
authors.lastname: Bott
authors.forename: Leszek
authors.initials: L
authors.lastname: Helczynski
authors.forename: David
authors.initials: D
authors.lastname: Ulmert
authors.forename: Yuzhuo
authors.initials: Y
authors.lastname: Wang
authors.forename: Yuanjie
authors.initials: Y
authors.lastname: Niu
authors.forename: Colin
authors.initials: C
authors.lastname: Collins
authors.forename: Amilcar
authors.initials: A
authors.lastname: Flores-Morales
mesh_terms: D045744:Cell Line, Tumor; D054338:Cell Transdifferentiation; D002843:Chromatin / Q000378:metabolism; D056970:Co-Repressor Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000032:analysis / Q000276:immunology / Q000378:metabolism*
chemical_list: D002843:Chromatin; D056970:Co-Repressor Proteins; D009419:Nerve Tissue Proteins; C121019:RCOR1 protein, human; D011944:Receptors, Androgen; D012097:Repressor Proteins