Unveiling the association of STAT3 and HO-1 in prostate cancer: role beyond heme degradation

Neoplasia. 2012 Nov;14(11):1043-56. doi: 10.1593/neo.121358.


Activation of the androgen receptor (AR) is a key step in the development of prostate cancer (PCa). Several mechanisms have been identified in AR activation, among them signal transducer and activator of transcription 3 (STAT3) signaling. Disruption of STAT3 activity has been associated to cancer progression. Recent studies suggest that heme oxygenase 1 (HO-1) may play a key role in PCa that may be independent of its catalytic function. We sought to explore whether HO-1 operates on AR transcriptional activity through the STAT3 axis. Our results display that HO-1 induction in PCa cells represses AR activation by decreasing the prostate-specific antigen (PSA) promoter activity and mRNA levels. Strikingly, this is the first report to show by chromatin immunoprecipitation analysis that HO-1 associates to gene promoters, revealing a novel function for HO-1 in the nucleus. Furthermore, HO-1 and STAT3 directly interact as determined by co-immunoprecipitation studies. Forced expression of HO-1 increases STAT3 cytoplasmic retention. When PCa cells were transfected with a constitutively active STAT3 mutant, PSA and STAT3 downstream target genes were abrogated under hemin treatment. Additionally, a significant decrease in pSTAT3 protein levels was detected in the nuclear fraction of these cells. Confocal microscopy images exhibit a decreased rate of AR/STAT3 nuclear co-localization under hemin treatment. In vivo studies confirmed that STAT3 nuclear delimitation was significantly decreased in PC3 tumors overexpressing HO-1 grown as xenografts in nude mice. These results provide a novel function for HO-1 down-modulating AR transcriptional activity in PCa, interfering with STAT3 signaling, evidencing its role beyond heme degradation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cytoplasm / metabolism
  • Disease Models, Animal
  • Gene Expression
  • Heme / metabolism*
  • Heme Oxygenase-1 / genetics
  • Heme Oxygenase-1 / metabolism*
  • Humans
  • Male
  • Matrix Metalloproteinase 9 / metabolism
  • Mice
  • Promoter Regions, Genetic
  • Prostate-Specific Antigen / genetics
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / metabolism*
  • Protein Binding
  • Protein Transport
  • Receptors, Androgen / metabolism
  • STAT3 Transcription Factor / metabolism*
  • Signal Transduction
  • Transplantation, Heterologous


  • Receptors, Androgen
  • STAT3 Transcription Factor
  • Heme
  • Heme Oxygenase-1
  • Prostate-Specific Antigen
  • Matrix Metalloproteinase 9