Estrogen receptor β sustains epithelial differentiation by regulating prolyl hydroxylase 2 transcription

Abstract

Estrogen receptor β (ERβ) promotes the degradation of hypoxia inducible factor 1α (HIF-1α), which contributes to the ability of this hormone receptor to sustain the differentiation of epithelial and carcinoma cells. Although the loss of ERβ and consequent HIF-1 activation occur in prostate cancer with profound consequences, the mechanism by which ERβ promotes the degradation of HIF-1α is unknown. We report that ERβ regulates the ligand (3β-adiol)-dependent transcription of prolyl hydroxylase 2 (PHD2) also known as Egl nine homolog 1 (EGLN1), a 2-oxoglutarate-dependent dioxygenase that hydroxylates HIF-1α and targets it for recognition by the von Hippel-Lindau tumor suppressor and consequent degradation. ERβ promotes PHD2 transcription by interacting with a unique estrogen response element in the 5′ UTR of the PHD2 gene that functions as an enhancer. PHD2 itself is critical for maintaining epithelial differentiation. Loss of PHD2 expression or inhibition of its function results in dedifferentiation with characteristics of an epithelial-mesenchymal transition, and exogenous PHD2 expression in dedifferentiated cells can restore an epithelial phenotype. Moreover, expression of HIF-1α in cells that express PHD2 does not induce dedifferentiation but expression of HIF-1α containing mutations in the proline residues that are hydroxylated by PHD2 induces dedifferentiation. These data describe a unique mechanism for the regulation of HIF-1α stability that involves ERβ-mediated transcriptional regulation of PHD2 and they highlight an unexpected role for PHD2 in maintaining epithelial differentiation.T he role of estrogen receptors (ERs), which are transcription factors belonging to the steroid/thyroid nuclear receptor superfamily (1-3), in regulating epithelial differentiation is an emerging area of considerable biological interest and pathological relevance. In the prostate, the discovery of ERβ (4, 5) has generated intense interest in the roles played by this ER in several tissues including prostate and breast epithelia (6-11). Increasing evidence supports the hypothesis that ERβ functions to maintain epithelial differentiation in the prostate and breast (9,10,12,13). In the normal prostate, ERβ contributes to epithelial differentiation as evidenced by the observation that ERβ knockout mice exhibit altered differentiation in the ventral prostate, whereas the glands of ERα knockout mice lack these lesions and appear to be normal (12). ERβ in human prostate cancer is of substantial relevance because there is an inverse relationship between the expression of ERβ and highly invasive prostate cancer (9,14). In pursuit of a functional basis for this relationship, we demonstrated that ERβ sustains an epithelial phenotype and impedes a mesenchymal transition in prostate cancer and we identified a metabolite of dihydrotestosterone, 5α-androstane-3β,17β4-diol (3β-adiol) as the specific ERβ ligand that mediates this function (9). This observation is in agreement with the recent findings that 3β-adiol is a natural ligand for ERβ in ...

Estrogen receptor beta in prostate cancer: friend or foe?

“…The principle ligand of ERB in the prostate is 5a-androstane-3b,17b-diol (3b-diol), a metabolite of 5a-dihydrotestosterone (DHT) (Oliveira et al 2007). In prostate cell lines (benign and cancer) ERB has been shown to maintain differentiation of epithelial cells by regulation of epithelial-mesenchymal transition (EMT) genes such as Twist via hypoxia-inducible factor 1 alpha (HIF-1A) (Mak et al 2013).…”

“…ERB expression is low in high-grade PIN of the prostate , reflecting its pre-malignant phenotype. It has been shown that as ERB expression declines with the development of prostate cancer, levels of HIF-1A increase, resulting in epithelial dedifferentiation and growth of high-grade, aggressive tumours (Mak et al 2013). Horvath et al (2001) showed in a study of 159 prostates obtained by radical prostatectomy that over 75% of tumours in their cohort did not express ERB.…”

The Role of Estrogen Receptor β in Prostate Cancer

“…The mechanisms through which ERβ maintain differentiation involve the degradation of hypoxia-inducible factor 1α (HIF-1α) (38). ERβ enhances transcription of prolyl hydroxylase domaincontaining protein 2 (PHD2) that hydroxylates HIF-1α and marks HIF for destruction by the von Hippel-Lindau tumor suppressor (VHL) (39). Additionally, ERβ appears to have antiproliferative actions which are independent from the alternations of systemic androgen concentration and the activation of ERα, as documented in aromatase-knockout mice treated with ERβ-specific agonists (40).…”

Insight into the mechanisms of action of estrogen receptor β in the breast, prostate, colon, and CNS

“…The reason for the negative effects of ERb2 is not clear but if it has actions, which are opposite to those of ERb (Dey et al 2012), then it might promote survival under the conditions of hypoxia. One of the mechanisms through which ERb exerts antiproliferative effects is its facilitation of HIF1a degradation (Mak et al 2013). The effects of ERb2 on the stability of HIF1a remain to be determined.…”