Heme oxygenase 1 (ho-1) inhibits androgen receptor activation by repressing stat3 signaling. HO-1 modulates gene expression in prostate cancer by repressing STAT3 signaling pathway.

BELEN ELGUERO; GERALDINE GUERON; ROBERTO MEISS; FEDERICO COLUCCIO LESKOW; JIMENA GIUDICE; ADRIANA DE SIERVI; ELBA VAZQUEZ

Edinburgh

Congreso; 7th International Congress on Heme Oxygenases and Related Enzymes; 2012

Prostate cancer (PCa) is the most commonly diagnosed cancer in men. Activation of the androgen receptor (AR) is a key step in the development and progression of PCa. Several mechanisms are involved in AR activation. Alterations in STAT3 activity have been associated to cancer progression. We recently demonstrated that heme oxygenase-1 (HO-1) over-expression induces its nuclear translocation and impairs PCa xenograft growth. The aim of the present study sought to determine whether HO-1 controls AR transcriptional activity through STAT signaling pathway. Our results revealed that HO-1 induction in LNCaP cells repressed the promoter activity and mRNA levels of PSA (prostate specific antigen) .ChIP analysis showed that HO-1 associates to the PSA promoter. Moreover, an interaction between STAT3 and HO-1 was detected by immunoprecipitation studies. When LNCaP cells were transfected with a constitutively active STAT3 mutant, the induced levels of PSA and Bcl XL were abrogated under hemin treatment. Furthermore, STAT3 mRNA levels were repressed when cells were exposed to hemin. Accordingly, a significant decrease in pSTAT3 protein levels were detected in the nuclear fraction of these cells, together with increased STAT3 cytoplasmic retention. Immunofluorescense microscopy and quantitative colocalization analysis showed that hemin decreased the AR and STAT3 nuclear colocalization in LNCaP cells Moreover, in vivo studies demonstrated that STAT3 nuclear expression was significantly decreased in PC3 tumors overexpressing HO-1 grown as xenografts in nude mice. These data demonstrate that HO-1 induction impairs STAT3 nuclear localization and abrogates its transcriptional activity, blocking AR signaling.