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.
Highlights
Prostate cancer is a slowly progressing disease, initially treatable with androgen- deprivation therapy (ADT) [1], but usually recurring in a more aggressive form that is androgen independent [2, 3]
The 22Rv1 and PC3 cell lines were obtained from the American Type Culture Collection (ATCC). 22Rv1 cells were maintained in RPMI-1640 (Invitrogen Inc., Carlsbad, CA) medium supplemented with 10% fetal bovine serum (FBS)
We have previously shown that ERβ2 increased expression of epithelial-to-mesenchymal transition (EMT)-associated genes Twist1 and Slug (SNAI2) in prostate cancer cells [15]
Summary
Prostate cancer is a slowly progressing disease, initially treatable with androgen- deprivation therapy (ADT) [1], but usually recurring in a more aggressive form that is androgen independent [2, 3]. Most aggressive prostate cancers express high levels of androgen receptor (AR) and, in addition, utilize a variety of mechanisms to activate AR in the absence of its ligand. The cancer can acquire the ability to synthesize AR ligands, phosphorylate AR or, through alternative splicing, create a constitutively active AR [4]. Expression of the main isoform of estrogen receptor β (ERβ/ESR2), ERβ1, is reduced during prostate cancer progression [5,6,7,8]. ERβ1 has been shown to down-regulate the expression of AR, so upon.
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