Androgen receptor interacts with a novel MYST protein, HBO1

ArticleinJournal of Biological Chemistry 275(45):35200-8 · December 2000with8 Reads
DOI: 10.1074/jbc.M004838200 · Source: PubMed
The androgen receptor (AR), a member of the nuclear receptor superfamily, plays a central role in male sexual differentiation and prostate cell proliferation. Results of treating prostate cancer by androgen ablation indicate that signals mediated through AR are critical for the growth of these tumors. Like other nuclear receptors, AR exerts its transcriptional function by binding to cis-elements upstream of promoters and interacting with other transcriptional factors (e.g. activators, repressors and modulators). To determine the mechanism of AR-regulated transcription, we used the yeast two-hybrid system to identify AR-associated proteins. One of the proteins we identified is identical to the human origin recognition complex-interacting protein termed HBO1. A ligand-enhanced interaction between AR and HBO1 was further confirmed in vivo and in vitro. Immunofluorescence experiments showed that HBO1 is a nuclear protein, and Northern blot analysis revealed that it is ubiquitously expressed, with the highest levels present in human testis. HBO1 belongs to the MYST family, which is characterized by a highly conserved C2HC zinc finger and a putative histone acetyltransferase domain. Surprisingly, two yeast members of the MYST family, SAS2 and SAS3, have been shown to function as transcription silencers, despite the presence of the histone acetyltransferase domain. Using a GAL4 DNA-binding domain assay, we mapped a transcriptional repression domain within the N-terminal region of HBO1. Transient transfection experiments revealed that HBO1 specifically repressed AR-mediated transcription in both CV-1 and PC-3 cells. These results indicate that HBO1 is a new AR-interacting protein capable of modulating AR activity. It could play a significant role in regulating AR-dependent genes in normal and prostate cancer cells.

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  • ... These drugs overall exert their anticancer activity by favoring the acetylation and reversing the excess his Table 2 Examples of genes probably silenced by HDACs and inhibitors utilized for gene reexpression. Gene Cancer Cell lines Target protein Inhibitor Reference p21 Colon HDAC1 / HDAC2Huang et al. [69] Lung, gastric, colon HDAC1 / HDAC2 TSA / VPA / Butyrate Lin et al. [70] LungDepsipeptide / TSA Zhao [71] [78] E-cadherin Pancreatic HDAC1 / HDAC2 TSA VPA Von Burstin et al. [79] Nasopharyngeal HDAC1 / HDAC2Tong et al. [80] Ovarian HDAC1 / HDAC3 TSA / Apicidin / SAHA Hayashi et al. [61] DTWD1 Gastric HDAC3 TSA Ma et al. [81] PUMA Gastric HDAC3 TSA Feng et al. [82] 5-HTT Hepatic, lymphoma, myelomonocytic tumor P300/CBP P300 p53Glioma, ovarian, breast, colorectal, lung and pancreatic cancer Gayther et al. [95] Cyclin E MelanomaBandyopadhyay et al. [96] RbColon and cervical cancer Iyer et al. [97] MYC Lung and hematopoietic cancerOgiwara et al. [98] p53, caspase-3 Gastric cancerShi et al. [99] ZNF384 Lymphoblastic leukemiaQian et al. [100] MYST Tip60 RbLung cancer Leduc et al. [101] P53Skin tumor Hobbs et al. [102] AR Prostate cancer Gaughan et al., 200296;Halkidou et al. [103,104] c-Myc T-cell leukemia/ LymphomaAwasthi [105] NF-B Metastasis Kim et al. [106] HBO1 AR Prostate cancerSharma et al. [107] NF-BLeukemia Contzler et al. [108] VHLRenal cancer Zhou et al. [109] MOZ Nrf2 Liver cancerOhta et al. [110] AML-1Leukemia Katsumoto et al. [111] tone deacetylation leading to re-expression of silenced genes and contributing to reverse the malignant phenotype [115]. The effects of HDACi in gene transcription are complex. ...
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