Hey1, a Mediator of Notch Signaling, Is an Androgen Receptor Corepressor

Abstract

Hey1 is a member of the basic helix-loop-helix-Orange family of transcriptional repressors that mediate Notch signaling. Here we show that transcription from androgen-dependent target genes is inhibited by Hey1 and that expression of a constitutively active form of Notch is capable of repressing transactivation by the endogenous androgen receptor (AR). Our results indicate that Hey1 functions as a corepressor for AF1 in the AR, providing a mechanism for cross talk between Notch and androgen-signaling pathways. Hey1 colocalizes with AR in the epithelia of patients with benign prostatic hyperplasia, where it is found in both the cytoplasm and the nucleus. In marked contrast, we demonstrate that Hey1 is excluded from the nucleus in most human prostate cancers, raising the possibility that an abnormal Hey1 subcellular distribution may have a role in the aberrant hormonal responses observed in prostate cancer.

Human ASH1 expression in prostate cancer with neuroendocrine differentiation

“…However, recent reports aimed to define possible mechanisms leading to hormone resistance in prostate cancer identified specific alterations (cytoplasmic vs nuclear localization) of Notch modulators in prostate cancer, namely Hey1, which acts as corepressor of androgen receptor-mediated signaling and represses bHLH transcription factors, such as hASH1. 32 Abnormalities of Notch itself or Notch-positive effectors might be responsible for both the development of androgen-independent prostate cancers as well as of the de-repression of hASH1 transcriptional activities with the development of neuroendocrine-differentiated tumor clones. In this respect, our data on the lack of correlation between Notch1 and Hes1 and the presence of neuroendocrine phenotype in prostate tissues is inconclusive, and more detailed experiments are needed to clarify the activation status of such molecules in prostate cancer with neuroendocrine differentiation.…”

Inability of NCoR/SMRT to repress androgen receptor transcriptional activity in prostate cancer cell lines

“…In prostate cancer tissue, Hey1 localization was predominantly restricted to the cytoplasm. This localization is thought to abolish the repressive function of Hey1 on AR transcriptional activity (8). Prohibitin, another repressor of AR signaling, was shown to be downregulated by androgen treatment.…”

c-Jun enhancement of androgen receptor transactivation is associated with prostate cancer cell proliferation

“…Interestingly, the dimerization of AR, like other nuclear receptors, is driven by the D box in the second zincfinger of the DNA-binding domain (Haelens et al, 2003). Other AR repressors include histone deacetylase 1 (HDAC1) (Korkmaz et al, 2004), Hey1 (Belandia et al, 2005), PIASg (Gross et al, 2004), silencing mediator for retinoic acid and thyroid hormone receptor (SMRT) (Dotzlaw et al, 2002), and HBO1 (Sharma et al, 2000). AR coactivators include SRC-1 (Onate et al, 1998), TIF2 (Berrevoets et al, 1998), SRC-3 (also known as RAC3 or AIB1) (Zhou et al, 2005), and CBP (Aarnisalo et al, 1998), all of which are overexpressed in prostate cancer (Culig et al, 2004).…”