Abstract
We examined the regulation of NF-κB in prostate cancer by estrogen receptor β (ERβ) based on the inverse correlation between p65 and ERβ expression that exists in prostate carcinomas and reports that ERβ can inhibit NF-κB activation, although the mechanism is not known. We demonstrate that ERβ functions as a gate-keeper for NF-κB p65 signaling by repressing its expression and nuclear translocation. ERβ regulation of NF-κB signaling is mediated by HIF-1. Loss of ERβ or hypoxia stabilizes HIF-1α, which we found to be a direct driver of IKKβ transcription through a hypoxia response element present in the promoter of the IKKβ gene. The increase of IKKβ expression in ERβ-ablated cells correlates with an increase in phospho-IκBα and concomitant p65 nuclear translocation. An inverse correlation between the expression of ERβ and IKKβ/p65 was also observed in the prostates of ERβ knockout (BERKO) mice, Gleason grade 5 prostate tumors and analysis of prostate cancer databases. These findings provide a novel mechanism for how ERβ prevents NF-κB activation and raise the exciting possibility that loss of ERβ expression is linked to chronic inflammation in the prostate, which contributes to the development of high-grade prostate cancer.
Highlights
Chronic inflammatory diseases are known to cause epithelial malignancies including prostate cancer [1, 2]
Our data reveal that estrogen receptor β (ERβ) functions as a repressor of HIF-1α-mediated NFkB activation and support the possibility that ERβ may www.impactjournals.com/oncotarget contribute to the prevention of chronic inflammation in the prostate and prostate cancer
To understand how p65 nuclear translocation is regulated by ERβ signaling, we focused on the IKKβ/IκBα canonical pathway
Summary
Chronic inflammatory diseases are known to cause epithelial malignancies including prostate cancer [1, 2]. Once activated by external stimuli such as cytokines, lipopolysaccharide or viruses, IκB kinases (IKKβ) phosphorylate IκBα, which is degraded by the proteasome [8] This cascade event allows the translocation of the p65.p50 complex to the nucleus where it regulates the transcription of its target genes. There is a functional link between the expression of HIF-1α and p65 in several cancers [11, 12], which is consistent with the fact that hypoxia and inflammation are common features of all solid tumors [13] For these reasons, we examined the hypothesis that ERβ repression of the NF-kB pathway involves HIF-1α. Our data reveal that ERβ functions as a repressor of HIF-1α-mediated NFkB activation and support the possibility that ERβ may www.impactjournals.com/oncotarget contribute to the prevention of chronic inflammation in the prostate and prostate cancer
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