This study underlines the importance of HDAC1 in cell proliferation and the development of prostate cancer (CaP) and proposes a mechanism for HDAC1 nuclear recruitment. HDAC1 may constitute a crucial therapeutic target particularly in the most lethal phase of androgen independence.

The androgen receptor (AR), a member of the nuclear hormone receptor superfamily, is thought to play an important role in the development of prostate cancer. The AR is a hormone-dependent transcription factor that activates expression of numerous androgen-responsive genes. Histone acetyltransferase-containing proteins have been shown to increase activity of several transcription factors, including nuclear hormone receptors, by eliciting histone acetylation, which facilitates promoter access to the transcriptional machinery. Conversely, histone deacetylases (HDACs) have been identified which reduce levels of histone acetylation and are associated with transcriptional repression by various transcription factors. We have previously shown that Tip60 (Tat-interactive protein, 60 kDa) is a bona fide co-activator protein for the AR. Here we show that Tip60 directly acetylates the AR, which we demonstrate is a requisite for Tip60-mediated transcription. To define a mechanism for repression of AR function, we demonstrate that AR activity is specifically down-regulated by the histone deacetylase activity of HDAC1. Furthermore, using both mammalian two-hybrid and immunoprecipitation experiments, we show that AR and HDAC1 interact, suggestive of a direct role for down-regulation of AR activity by HDAC1. In chromatin immunoprecipitation assays, we provide evidence that AR, Tip60, and HDAC1 form a trimeric complex upon the endogenous AR-responsive PSA promoter, suggesting that acetylation and deacetylation of the AR is an important mechanism for regulating transcriptional activity.Prostate cell growth, development, and homeostasis are critically dependent upon the androgen receptor (AR), 1 an androgen-responsive transcription factor that activates expression of target genes in response to hormonal signals derived from the testis. The AR is a member of the nuclear hormone receptor (NHR) family and, in common with other family members, is a modular protein composed of numerous independently functioning domains (1-3). Upon binding to androgens within the cytoplasm, the AR translocates to the nucleus (4) where it recognizes and binds specific promoter elements and activates transcription of target genes through the concerted action of two transcriptional activation domains, namely activation function-1 (AF-1) and -2 (AF-2) (5).The AF-2 domain of NHRs plays a fundamental role in receptor-mediated transcriptional activation. Upon ligandbinding, the C-terminal AF-2 undergoes a shift in conformation generating a platform suitable for protein-protein interaction with co-activator molecules (6, 7). To date, numerous co-activator molecules have been identified that function to enhance the transcriptional potential of NHRs (8). The majority of coactivators identified share the capacity to elicit histone acetyltransferase (HAT) activity, a catalytic process heavily implicated in target gene activation via chromatin remodeling (9, 10). Of the identified HAT-containing co-activators, several have emerged to play significant roles in NHR act...

The androgen receptor (AR) is a member of the nuclear hormone receptor superfamily. Recent work in this field has been focused upon defining the mechanisms of transcriptional control exacted by members of this superfamily. Using a COOH-terminal region of the human AR in a yeast two-hybrid screen, we have identified Tip60 as an AR-interacting protein. In this report, we show that Tip60, which was originally identified as a coactivator for the human immunodeficiency virus TAT protein, can enhance AR-mediated transactivation in a ligand-dependent manner in LNCaP and COS-1 cell lines. In addition, our experiments show that Tip60 can also enhance transactivation through the estrogen receptor and progesterone receptor in a ligand-dependent manner; thus identifying Tip60 as a nuclear hormone receptor coactivator. Our studies also demonstrate that Tip60 co-immunoprecipitates with the full-length AR in vitro and that, in our system, Tip60 enhances transactivation to levels observed with the coactivators steroid receptor coactivator 1, p300, and CREB-binding protein.The importance of such proteins in enhancing nuclear hormone receptor-mediated transcriptional activation is widely accepted, and this work suggests that Tip60 may have an equally important role to play. The AR1 is a member of the nuclear hormone receptor superfamily of ligand-dependent transcription factors. In the nucleus, the ligand-activated receptors bind to their cognate response elements in or near promoter regions of target genes to positively or negatively regulate gene expression (reviewed in Ref.

Transrectal ultrasonography of ovaries was performed each day in non-prolific Western white-faced (n = 12) and prolific Finn ewes (n = 7), during one oestrous cycle in the middle portion of the breeding season (October-December), to record the number and size of all follicles > or = 3 mm in diameter. Blood samples collected once a day were analysed by radioimmunoassay for concentrations of LH, FSH and oestradiol. A cycle-detection computer program was used to identify transient increases in concentrations of FSH and oestradiol in individual ewes. Follicular and hormonal data were then analysed for associations between different stages of the lifespan of the largest follicles of follicular waves, and detected fluctuations in serum concentrations of FSH and oestradiol. A follicular wave was defined as a follicle or a group of follicles that began to grow from 3 to > or = 5 mm in diameter within a 48 h period. An average of four follicular waves per ewe emerged during the interovulatory interval in both breeds of sheep studied. The last follicular wave of the oestrous cycle contained ovulatory follicles in all ewes, and the penultimate wave contained ovulatory follicles in 10% of white-faced ewes but in 57% of Finn ewes. Transient increases in serum concentrations of FSH were detected in all animals and concentrations reached peak values on days that approximated to follicle wave emergence. Follicular wave emergence was associated with the onset of transient increases in serum concentrations of oestradiol, and the end of the growth phase of the largest follicles (> or = 5 mm in diameter) was associated with peak serum concentrations of oestradiol. Serum FSH concentrations were higher in Finn than in Western white-faced ewes during the follicular phase of the cycle (P < 0.05). There were no significant differences in serum concentrations of LH between Western white-faced and Finn ewes (P > 0.05). Mean serum concentrations of oestradiol were higher in Finn compared with Western white-faced ewes (P < 0.01). It was concluded that follicular waves (follicles growing from 3 to > or = 5 mm in diameter) occurred in both prolific and non-prolific genotypes of ewes and were closely associated with increased secretion of FSH and oestradiol. The increased ovulation rate in prolific Finn ewes appeared to be due primarily to an extended period of ovulatory follicle recruitment.