Acetylation of Androgen Receptor Enhances Coactivator Binding and Promotes Prostate Cancer Cell Growth

Department of Chemistry, University of Helsinki, Helsinki, Uusimaa, Finland
Molecular and Cellular Biology (Impact Factor: 4.78). 01/2004; 23(23):8563-75. DOI: 10.1128/MCB.23.23.8563-8575.2003
Source: PubMed


Modification by acetylation occurs at ε-amino lysine residues of histones and transcription factors. Unlike phosphorylation,
a direct link between transcription factor acetylation and cellular growth or apoptosis has not been established. We show
that the nuclear androgen receptor (AR), a DNA-binding transcriptional regulator, is acetylated in vivo. The acetylation of
the AR is induced by ligand dihydrotestosterone and by histone deacetylase (HDAC) inhibitors in living cells. Direct AR acetylation
augmented p300 binding in vitro. Constructs mimicking neutral polar substitution acetylation (ARK630Q, ARK630T) enhanced p300 binding and reduced N-CoR/HDAC/Smad3 corepressor binding, whereas charged residue substitution (ARK630R) reduced p300 binding and enhanced corepressor binding. The AR acetylation mimics promoted cell survival and growth of prostate
cancer cells in soft agar and in nude mice and augmented transcription of a subset of growth control target gene promoters.
Thus, transcription factor acetylation regulates coactivator/corepressor complex binding, altering expression of specific
growth control genes to promote aberrant cellular growth in vivo.

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Available from: Maria Laura Avantaggiati, Feb 22, 2014
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    • "In the activation and to induce transcription activity of androgen receptor plays an important role coactivator p300. The p300 mediated acetylation of AR increases potential of this receptor to induce proliferation of prostate cells (Fu et al., 2003; Debes et al., 2005). Genetic, biochemical and functional data suggest that some of coregulators may be important regulators for some groups of NR-regulated genes (Glass and Rosenfeld, 2000), e.g. "
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    ABSTRACT: Sodium butyrate, as a naturally occurring inhibitor of histone deacetylases (HDACI), is a non-toxic agent, with an ability to change histone acetylation and expression of large number genes. This study shows different effects of sodium butyrate on expression and transcription activity of the androgen receptor in cancer (LNCaP, C4-2) and normal (RWPE-1) prostate cells. Moreover, we studied the coregulator expressions and histone acetylation alteration in cancer and normal cells. Coregulators, coactivators as well as corepressors, play an important role in AR-mediated growth and progression of prostate cancer. There is a competition between coactivators and corepressors for binding on the AR and therefore the changes in coregulators expression and ratio could be important for prostate cancer survival. Our study was focused on two coregulators, SMRT and p300, which interact with AR in multiprotein complex and affect the AR transcription activity. Our data indicate that sodium butyrate has an effect on AR coregulators expression, transcription activity and histone acetylation in cancer cells, but there is only minimal effect in normal cells. In addition, the results of changes in acetylation level on lysine residues of histone H4 after sodium butyrate treatment confirm its epigenetic effect on prostate cancer cells.
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    • "In contrast, p300, another AR activator, was not able to derepress COUP-TF II-induced suppression of AR transactivation. This is consistent with the fact that p300 activates AR transactivation by inducing the open-structure of chromatin through histone acetylation [47], [55], but not by bridging the DBD/LBD complex of AR. This notion is further supported by our results showing that the HDAC inhibitors TSA, NaBut, and NIC were not able to recover the COUP-TF II-induced repression of AR transactivation. "
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    ABSTRACT: Androgen receptor (AR) is involved in the development and progression of prostate cancers. However, the mechanisms by which this occurs remain incompletely understood. In previous reports, chicken ovalbumin upstream promoter-transcription factor II (COUP-TF II) has been suggested to play a role in the development of cancers. In the present study, we explored a putative role of COUP-TF II in prostate cancers by investigating its effect on cell proliferation and a cross-talk between COUP-TF II and AR. Overexpression of COUP-TF II results in the inhibition of androgen-dependent proliferation of prostate cancer cells. Further studies show that COUP-TF II functions as a corepressor of AR. It represses AR transactivation on target promoters containing the androgen response element (ARE) in a dose-dependent manner. In addition, COUP-TF II interacts physically with AR in vitro and in vivo. It binds to both the DNA binding domain (DBD) and the ligand-binding domain (LBD) of AR and disrupts the N/C terminal interaction of AR. Furthermore, COUP-TF II competes with coactivators such as ARA70, SRC-1, and GRIP1 to modulate AR transactivation as well as inhibiting the recruitment of AR to its ARE-containing target promoter. Taken together, our findings suggest that COUP-TF II is a novel corepressor of AR, and provide an insight into the role of COUP-TF II in prostate cancers.
    Preview · Article · Nov 2012 · PLoS ONE
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    • "Similarly, a Tip60 gene knockout study proposed Tip60 as a haplo-insufficient tumour suppressor at pre and early-tumoral stages of lymphoma, breast and head and neck cancers [16]. However, studies on clinical prostate specimens contradict this suggestion and support Tip60 as an oncogene in CaP [13], [17]. Thus, targeting the acetylase activity of Tip60 could be a useful therapeutic strategy in CaP. "
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    ABSTRACT: Tip60 (KAT5) is a histone acetyltransferase (HAT enzyme) involved in multiple cellular processes including transcriptional regulation, DNA damage repair and cell signalling. In prostate cancer, aggressive cases over-express Tip60 which functions as an androgen receptor co-activator via direct acetylation of lysine residues within the KLKK motif of the receptor hinge region. The purpose of this study was to identify and characterise a Tip60 acetylase inhibitor. High-throughput screening revealed an isothiazole that inhibited both Tip60 and p300 HAT activity. This substance (initially identified as 4-methyl-5-bromoisothiazole) and other isothiazoles were synthesised and assayed against Tip60. Although an authentic sample of 4-methyl-5-bromoisothiazole was inactive against Tip60, in an in vitro HAT assay, 1,2-bis(isothiazol-5-yl)disulfane (NU9056) was identified as a relatively potent inhibitor (IC(50) 2 µM). Cellular activity was confirmed by analysis of acetylation of histone and non-histone proteins in a prostate cancer cell line model. NU9056 treatment inhibited cellular proliferation in a panel of prostate cancer cell lines (50% growth inhibition, 8-27 µM) and induced apoptosis via activation of caspase 3 and caspase 9 in a concentration- and time-dependent manner. Also, decreased androgen receptor, prostate specific antigen, p53 and p21 protein levels were demonstrated in response to treatment with NU9056. Furthermore, pre-treatment with NU9056 inhibited both ATM phosphorylation and Tip60 stabilization in response to ionising radiation. Based on the activity of NU9056 and the specificity of the compound towards Tip60 relative to other HAT enzymes, these chemical biology studies have identified Tip60 as a potential therapeutic target for the treatment of prostate cancer.
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