title: ELF3 is a repressor of androgen receptor action in prostate cancer cells.
abstract: The androgen receptor (AR) has a critical role in the development and progression of prostate cancer (PC) and is a major therapeutic target in this disease. The transcriptional activity of AR is modulated by the coregulators with which it interacts, and consequently deregulation of cofactor expression and/or activity impacts the expression of genes whose products can have a role in PC pathogenesis. Here we report that E74-like factor 3 (ELF3), a member of the ETS family of transcription factors, is a repressor of AR transcriptional activity. Exogenous expression of ELF3 represses AR transcriptional activity when assessed using reporter-based transfection assays or when evaluated on endogenous AR target genes. Conversely, ELF3 knock down increases the AR transcriptional activity. Biochemical dissection of this activity indicates that it results from the physical interaction between ELF3 and AR and that this interaction inhibits the recruitment of AR to specific androgen response elements within target gene promoters. Significantly, we observed that depletion of ELF3 expression in LNCaP cells promotes cell migration, whereas increased ELF3 expression severely inhibits tumor growth in vitro and in a mouse xenograft model. Taken together, these results suggest that modulation of ELF3 expression and/or AR/ELF3 interaction may have utility in the treatment of PC.
authors: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
authors: A
authors: A
authors: Shatnawi
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors: J D
authors: JD
authors: Norris
authors: Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada.
authors: C
authors: C
authors: Chaveroux
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors: J S
authors: JS
authors: Jasper
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors: A B
authors: AB
authors: Sherk
authors: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC, USA.
authors: D P
authors: DP
authors: McDonnell
authors: 1] Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada. [2] Departments of Biochemistry, Medicine and Oncology, McGill University, Montréal, Québec, Canada.
authors: V
authors: V
authors: Giguère
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000502:physiology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D011518:Proto-Oncogene Proteins / Q000737:chemistry / Q000502:physiology*; D050783:Proto-Oncogene Proteins c-ets; D011944:Receptors, Androgen / Q000378:metabolism*; D012097:Repressor Proteins / Q000502:physiology; D020218:Response Elements; D014157:Transcription Factors / Q000737:chemistry / Q000502:physiology*; D014158:Transcription, Genetic; D047368:Tumor Burden
chemical_list: D004268:DNA-Binding Proteins; C105529:ELF3 protein, human; D011518:Proto-Oncogene Proteins; D050783:Proto-Oncogene Proteins c-ets; D011944:Receptors, Androgen; D012097:Repressor Proteins; D014157:Transcription Factors