title: Early Growth Response 3 regulates genes of inflammation and directly activates IL6 and IL8 expression in prostate cancer.
abstract: BACKGROUND
  Transcription factor EGR3 (Early Growth Response 3) is a little-studied member of the EGR family that is highly expressed in human prostate tumours compared with normal tissue. Its function in prostate cancer, however, is unknown.
  
  
  METHODS
  Stable shRNA silencing was achieved in naturally overexpressing prostate cancer cells, followed by Affymetrix expression analysis. Fold changes of ⩾2 and ⩽-2 were considered valid and t-tests P-values of ⩽0.01 were considered statistically significant. Potential EGR3 target genes were validated by real-time qPCR, chromatin immunoprecipitation, and gain-of-function experiments. Promoter analysis confirmed the presence of consensus binding sites in the promoters of target genes.
  
  
  RESULTS
  Early Growth Response 3 regulates the expression of ∼330 genes, 35% of which are involved in immune responses and inflammatory processes, and 15% crosstalk with the NF-κB signalling pathway. In particular, EGR3 induces the expression of over 50 secreted cytokines, growth factors, and matrix remodelling factors. Two interleukins of great relevance to prostate cancer, IL6 and IL8, were further validated as EGR3 target genes: both promoters contain EGR consensus binding sites and are pulled down in intact cells by EGR3 chromatin immunoprecipitation. Silencing of EGR3 decreased IL6 and IL8 expression, whereas overexpression of EGR3 in nontransformed cells induced IL6 and IL8 expression.
  
  
  CONCLUSIONS
  Chronic inflammation plays a critical role in prostate cancer and elevated production of pro-inflammatory cytokines IL8 and IL6, in particular, contributes to disease progression and to the onset of castration resistance. It is shown for the first time that EGR3 is involved in the upregulation of both IL6 and IL8. Together with our previous observation that EGR3 is highly expressed in prostate tumours compared with normal tissue and strongly correlates with IL6 and IL8 expression in clinical samples, the present study suggests that EGR3 promotes excessive production of IL6 and IL8 observed during the progression of prostate cancer.
authors: Vaccine Research Institute of San Diego, San Diego, CA 92109, USA.
authors: V T
authors: VT
authors: Baron
authors: Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92067-4800, USA.
authors: R
authors: R
authors: Pio
authors: Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92067-4800, USA.
authors: Z
authors: Z
authors: Jia
authors: Department of Pathology and Laboratory Medicine, University of California, Irvine, Irvine, CA 92067-4800, USA.
authors: D
authors: D
authors: Mercola
mesh_terms: D051776:Early Growth Response Protein 3 / Q000502:physiology*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D015850:Interleukin-6 / Q000235:genetics*; D016209:Interleukin-8 / Q000235:genetics*; D008297:Male; D046228:Microarray Analysis; D011471:Prostatic Neoplasms / Q000235:genetics*; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured
chemical_list: C508606:CXCL8 protein, human; C079945:EGR3 protein, human; C508600:IL6 protein, human; D015850:Interleukin-6; D016209:Interleukin-8; D051776:Early Growth Response Protein 3
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