ERbeta regulation of NF-kB activation in prostate cancer is mediated by HIF-1

We examined the regulation of NF-kappaB in prostate cancer by estrogen receptor beta (ERbeta) based on the inverse correlation between p65 and ERbeta expression that exists in prostate carcinomas and reports that ERbeta can inhibit NF-kappaB activation, although the mechanism is not known. We demonstrate that ERbeta functions as a gate-keeper for NF-kappaB p65 signaling by repressing its expression and nuclear translocation. ERbeta regulation of NF-kappaB signaling is mediated by HIF-1. Loss of ERbeta or hypoxia stabilizes HIF-1alpha, which we found to be a direct driver of IKKbeta transcription through a hypoxia response element present in the promoter of the IKKbeta gene. The increase of IKKbeta expression in ERbeta-ablated cells correlates with an increase in phospho-IkappaBalpha and concomitant p65 nuclear translocation. An inverse correlation between the expression of ERbeta and IKKbeta/p65 was also observed in the prostates of ERbeta knockout (BERKO) mice, Gleason grade 5 prostate tumors and analysis of prostate cancer databases. These findings provide a novel mechanism for how ERbeta prevents NF-kappaB activation and raise the exciting possibility that loss of ERbeta expression is linked to chronic inflammation in the prostate, which contributes to the development of high-grade prostate cancer