Estrogen Receptor β2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1α in Prostate Cancer

Prasenjit Dey; Laura A Velazquez-Villegas; Michelle Faria; Anthony Turner; Philp Jonsson; Paul Webb; Cecilia Williams; Jan-Åke Gustafsson; Anders M Ström

doi:10.1371/journal.pone.0128239

Estrogen Receptor β2 Induces Hypoxia Signature of Gene Expression by Stabilizing HIF-1α in Prostate Cancer

PLoS One. 2015 May 26;10(5):e0128239. doi: 10.1371/journal.pone.0128239. eCollection 2015.

Authors

Prasenjit Dey¹, Laura A Velazquez-Villegas¹, Michelle Faria¹, Anthony Turner¹, Philp Jonsson¹, Paul Webb², Cecilia Williams³, Jan-Åke Gustafsson⁴, Anders M Ström¹

Affiliations

¹ University of Houston, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, 3605 Cullen Boulevard, Science & Engineering Research Center, Bldg 545, Houston, Texas 77204-5056, United States of America.
² Genomic Medicine Program, Houston Methodist Research Institute, Weill Cornell Medical College, Houston, TX 77030, United States of America.
³ University of Houston, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, 3605 Cullen Boulevard, Science & Engineering Research Center, Bldg 545, Houston, Texas 77204-5056, United States of America; Science for Life Laboratory, Department of Proteomics and Nanotechnology, KTH-Royal Institute of Technology, 171 21 Stockholm, Sweden.
⁴ University of Houston, Department of Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, 3605 Cullen Boulevard, Science & Engineering Research Center, Bldg 545, Houston, Texas 77204-5056, United States of America; Department of BioSciences and Nutrition, Karolinska Institutet, Novum, S-141 57 Huddinge, Sweden.

Abstract

The estrogen receptor (ER) β variant ERβ2 is expressed in aggressive castration-resistant prostate cancer and has been shown to correlate with decreased overall survival. Genome-wide expression analysis after ERβ2 expression in prostate cancer cells revealed that hypoxia was an overrepresented theme. Here we show that ERβ2 interacts with and stabilizes HIF-1α protein in normoxia, thereby inducing a hypoxic gene expression signature. HIF-1α is known to stimulate metastasis by increasing expression of Twist1 and increasing vascularization by directly activating VEGF expression. We found that ERβ2 interacts with HIF-1α and piggybacks to the HIF-1α response element present on the proximal Twist1 and VEGF promoters. These findings suggest that at least part of the oncogenic effects of ERβ2 is mediated by HIF-1α and that targeting of this ERβ2 - HIF-1α interaction may be a strategy to treat prostate cancer.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cell Hypoxia / genetics
Cell Line, Tumor
Estrogen Receptor beta / genetics
Estrogen Receptor beta / metabolism*
Gene Expression Regulation, Neoplastic*
Humans
Hypoxia-Inducible Factor 1, alpha Subunit / genetics
Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
Male
Neoplasm Metastasis
Neoplasm Proteins / genetics
Neoplasm Proteins / metabolism*
Nuclear Proteins / genetics
Nuclear Proteins / metabolism
Prostatic Neoplasms / genetics
Prostatic Neoplasms / metabolism*
Prostatic Neoplasms / pathology
Protein Stability
Response Elements*
Twist-Related Protein 1 / genetics
Twist-Related Protein 1 / metabolism

Substances

ESR2 protein, human
Estrogen Receptor beta
HIF1A protein, human
Hypoxia-Inducible Factor 1, alpha Subunit
Neoplasm Proteins
Nuclear Proteins
TWIST1 protein, human
Twist-Related Protein 1

Grants and funding

This work was supported by The Cancer Prevention & Research Institute of Texas (CPRIT) grants HIRP100680 and RP110444, the Texas Emerging Technology Fund under Agreement no. 300-9-1958, the Robert A. Welch Foundation (Grant E-0004), the Swedish Cancer Fund and Marie Curie Actions FP7-PEOPLE-2011-COFUND (GROWTH 291795) via the VINNOVA programme Mobility for Growth (to C.W.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.