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

Department of Oncology, Lombardi Cancer Center, Georgetown University, Washington, DC 20057, USA.
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 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.
    PLoS ONE 11/2012; 7(11):e49026. DOI:10.1371/journal.pone.0049026 · 3.23 Impact Factor
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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.
    PLoS ONE 10/2012; 7(10):e45539. DOI:10.1371/journal.pone.0045539 · 3.23 Impact Factor
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    • "Acetylation of steroid receptors results in either transcriptional activation or repression, depending on alterations in DNA binding affinities, coregulator recruitment, or hormone responsiveness [16,70-72]. Acetylation and SUMOylation can in theory compete for the same Lys residue of some proteins [73]. "
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    ABSTRACT: Covalent modification of nuclear receptors by the Small Ubiquitin-like Modifier (SUMO) is dynamically regulated by competing conjugation/deconjugation steps that modulate their overall transcriptional activity. SUMO conjugation of progesterone receptors (PRs) at the N-terminal lysine (K) 388 residue of PR-B is hormone-dependent and suppresses PR-dependent transcription. Mutation of the SUMOylation motif promotes transcriptional synergy. The present studies address mechanisms underlying this transcriptional synergy by using SUMOylation deficient PR mutants and PR specifically deSUMOylated by Sentrin-specific proteases (SENPs). We show that deSUMOylation of a small pool of receptors by catalytically competent SENPs globally modulates the cooperativity-driven transcriptional synergy between PR observed on exogenous promoters containing at least two progesterone-response elements (PRE2). This occurs in part by raising PR sensitivity to ligands. The C-terminal ligand binding domain of PR is required for the transcriptional stimulatory effects of N-terminal deSUMOylation, but neither a functional PR dimerization interface, nor a DNA binding domain exhibiting PR specificity, are required. We conclude that direct and reversible SUMOylation of a minor PR protein subpopulation tightly controls the overall transcriptional activity of the receptors at complex synthetic promoters. Transcriptional synergism controlled by SENP-dependent PR deSUMOylation is dissociable from MAPK-catalyzed receptor phosphorylation, from SRC-1 coactivation and from recruitment of histone deacetylases to promoters. This will provide more information for targeting PR as a part of hormonal therapy of breast cancer. Taken together, these data demonstrate that the SUMOylation/deSUMOylation pathway is an interesting target for therapeutic treatment of breast cancer.
    BMC Molecular Biology 03/2012; 13(1):10. DOI:10.1186/1471-2199-13-10 · 2.19 Impact Factor
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