UMMS Affiliation

Department of Molecular, Cell and Cancer Biology

Date

11-24-2015

Document Type

Article

Disciplines

Cancer Biology | Male Urogenital Diseases | Neoplasms | Oncology

Abstract

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.

Rights and Permissions

Citation: Oncotarget. 2015 Oct 2. doi: 10.18632/oncotarget.5377. Link to article on publisher's site

DOI of Published Version

10.18632/oncotarget.5377

Comments

All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.

Related Resources

Link to Article in PubMed

Keywords

HIF-1, NFkB, estrogen receptor beta, prostate

Journal Title

Oncotarget

PubMed ID

26450901

Creative Commons License

Creative Commons Attribution 3.0 License
This work is licensed under a Creative Commons Attribution 3.0 License.

Share

COinS
 
 

To view the content in your browser, please download Adobe Reader or, alternately,
you may Download the file to your hard drive.

NOTE: The latest versions of Adobe Reader do not support viewing PDF files within Firefox on Mac OS and if you are using a modern (Intel) Mac, there is no official plugin for viewing PDF files within the browser window.