Functional Domain and Motif Analyses of Androgen Receptor Coregulator ARA70 and Its Differential Expression in Prostate Cancer

Hu, Yueh Chiang; Yeh, Shuyuan; Yeh, Shauh Der; Sampson, Erik R.; Huang, Jiaoti; Li, Peng; Hsu, Cheng Lung; Ting, Huei-Ju; Lin, Hui Kuan; Wang, Liang; Kim, Eungseok; Ni, Jing; Chang, Chawnshang

doi:10.1074/jbc.m401781200

Cited by 83 publications

(73 citation statements)

References 60 publications

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“…The positive signal was blocked by antigenic peptide, and preimmune serum showed no immunoreactivity above background. These data correlate well with previous reports demonstrating that whereas ARA70␣ expression is decreased, 8,21 total ARA70 (␣ and ␤) is increased in prostate cancer, 17 suggesting ARA70␤ expression is increased in cancer.…”

Section: Increased Expression Of Ara70␤ In Human Prostate Cancersupporting

confidence: 92%

“…A previous report also shows cytoplasmic localization of ARA70␤, although the antibody used in that experiment recognizes both ␣ and ␤ forms. 17 The localization of ARA70␤ in the cytoplasm may suggest an indirect or class II AR co-activator function, whereas ARA70␣ likely functions as classic nuclear or class I co-activator. 17 Together with its increased expression in prostate cancer, ARA70␤ stimulates prostate cancer growth in an androgen-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

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Stimulation of Prostate Cancer Cellular Proliferation and Invasion by the Androgen Receptor Co-Activator ARA70β

Peng

Chen

et al. 2008

The American Journal of Pathology

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ARA70 was first identified as a gene fused to the ret oncogene in thyroid carcinoma and subsequently as a co-activator for androgen receptor (AR). Two isoforms of ARA70 have been identified: a 70-kDa version called ARA70␣ and an internally spliced 35-kDa variant termed ARA70␤. We have previously reported that ARA70␣ expression is reduced in prostate cancer, and its overexpression inhibits proliferation of LNCaP prostate cancer cells. However, the function of the ARA70␤ isoform in prostate cancer is not understood. In this report we examined the effects of ARA70␤ on AR transcriptional regulation as well as prostate cancer cellular proliferation and invasion. Although both ARA70␣ and ARA70␤ functioned as transcriptional co-activators of AR in cell-based reporter assays, ARA70␤ overexpression, in contrast to ARA70␣, promoted prostate cancer cellular proliferation and invasion through Matrigel. Interestingly, genome-wide expression profiling of cells expressing ARA70␤ revealed an increase in the expression of genes involved in the control of cell division and adhesion, compatible with a role for ARA70␤ in proliferation and invasion. Consistent with its function in promoting cell growth and invasion, ARA70␤ expression was increased in prostate cancer. Our findings implicate ARA70␤ as a regulator of tumor cell growth and metastasis by affecting gene expression. The androgen receptor (AR) is a transcription factor that regulates prostate cell growth and differentiation.1 AR mediates transcription through a series of events including ligand binding, DNA binding to cognate androgen response elements (AREs), and interaction with various co-activators. This results in activation of the general transcriptional machinery. 2 Co-activators are components that are required for activator-dependent transcription but appear to be dispensable for basal transcription. AR co-activators are thought to facilitate AR-dependent transcription by linking the receptor to the basal transcription machinery or by modulating chromatin through methylation and acetylation.3,4 An increasing number of AR-interacting proteins have been identified, and several have been shown to function as AR co-activators in cellbased reporter assay. [5][6][7] Interestingly, a number of AR co-activators display diverse patterns of expression in prostate cancer. For example, the AR cofactors ARA24, PIAS1, 8 cyclinD1, 9 SRC1, 10 and FHL2 11 appear overexpressed, whereas ARA70 8 and ART-27 12 are reduced in human prostate cancers compared to adjacent benign tissue. In addition, although most co-factors are expressed in prostatic epithelium, ARA55 is expressed exclusively in prostatic stroma, with reduced expression in prostate cancer. These findings suggest that AR coactivators perform distinct functions in prostate growth.One of the earliest described AR co-activators is ARA70. It was initially identified as a gene fused to the ret oncogene 13,14 and subsequently characterized as an AR co-activator.15 ARA70 interacts with the AR ligand-binding domain (LBD) via an FXX...

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Section: Increased Expression Of Ara70␤ In Human Prostate Cancersupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Stimulation of Prostate Cancer Cellular Proliferation and Invasion by the Androgen Receptor Co-Activator ARA70β

Peng

Chen

et al. 2008

The American Journal of Pathology

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“…It is hypothesized that the increase in coactivator expression leads to an increase in AR-regulated gene expression, for instance, ARA70 increases AR expression, stability, and nuclear translocation. 52 Thus, overexpression and recruitment of coactivator proteins to the AR-binding sites may facilitate the progression of HR PCAs.…”

Section: Amplification Of the Armentioning

confidence: 99%

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Rubin

2008

Modern Pathology

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The clinical dilemma today in the management of prostate cancer (PCA) is to distinguish men who need definitive treatment from men who have indolent disease. As demonstrated most recently by the randomized Scandinavian trial evaluating the benefit of prostatectomy over Watchful Waiting, surgery significantly decreased the risk of death from PCA. However, this same study also suggests that 19 men need to be treated to benefit one man. Given the high prevalence of the disease, the aging of the population, and the potential morbidity of treatment, the ability to distinguish aggressive from indolent forms of PCA is critical. Treatment for advanced PCA begins with androgen ablation, but eventually hormone-refractory (HR) PCA emerges. Novel therapies are in various stages of clinical trials, including kinase inhibitors, antisense oligonucleotides, and inhibitors of heat-shock proteins. The discovery of novel therapeutic approaches is an active area of clinical research. Eliminating HR PCA before it advances is a high priority in the biomarker field. Therefore, the development of molecular signatures of lethal PCA are critical. In addition, the recent discovery that a significant percentage of PCAs harbor a TMPRSS2-ETS gene fusion suggests that targeting either the ETS transcription factors or the fusion product may offer a novel approach to therapy. However, in 2007, the mainstay of treatment for advanced PCA remains androgen ablation therapy as originally introduced in the early 1940s.

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“…Both SRC-1 and ARA70 are expressed in human prostate cancer cell lines and in normal prostate, in the luminal epithelial cells that also express AR (Gregory et al, 2001;Linja et al, 2001;Hu et al, 2004;Powell et al, 2004;Agoulnik et al, 2005). There is both in vitro and in vivo evidence that SRC-1 is required for optimal androgen signalling and growth in the prostate, since knockdown of SRC-1 attenuated growth and androgendependent gene expression in androgen-sensitive prostate cancer cell lines (Agoulnik et al, 2005), and SRC-1-null mice exhibit attenuation of androgenstimulated prostatic growth (Xu et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…At the mRNA level, however, decreased or unaltered SRC-1 levels in malignant versus benign prostate have been reported (Fujimoto et al, 2001;Linja et al, 2004;Maki et al, 2006). Studies on expression of ARA70 in prostate cancer are equally contradictory with the co-activator being found to be both upregulated at the protein level (Hu et al, 2004) and downregulated at the RNA level (Li et al, 2002) in tumours versus benign tissue, whereas others have found no change in mRNA levels (Mestayer et al, 2003). In light of the current study, a possible explanation of the conflicting results of such studies could be differences in hormonal treatment regimes in the patients.…”

Section: Discussionmentioning

confidence: 99%

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression

2007

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Prostate tumour growth depends on androgens; hence treatment includes androgen ablation and anti-androgens. Eventually tumours progress and in approximately 30% of patients this is associated with mutation of the androgen receptor. Several receptor variants associated with advanced disease show promiscuous activation by other hormones and anti-androgens. Such loss of specificity could promote receptor activation, hence tumour growth, in the absence of conventional ligands, explaining therapy failure. We aimed to elucidate mechanisms by which alternative ligands promote receptor activation. The three most commonly identified variants in tumours (with amino-acid substitutions H874Y, T877A and T877S) and wild-type receptor showed differences in co-activator recruitment dependent upon ligand and the interaction motif utilized. Co-expression and knockdown of co-activators that bind via leucine or phenylalanine motifs, combined with chromatin immunoprecipitation and quantitative PCR, revealed these preferences extend to co-activator recruitment in vivo and affect receptor activity at the transcriptional level, with subsequent effects on target gene regulation. The findings suggest that mutant receptors, activated by alternative ligands, drive growth via different mechanisms to androgenactivated wild-type receptor. Tumours may hence behave differently dependent upon any androgen receptor mutation present and what ligand is driving growth, as distinct subsets of genes may be regulated.

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Functional Domain and Motif Analyses of Androgen Receptor Coregulator ARA70 and Its Differential Expression in Prostate Cancer

Cited by 83 publications

References 60 publications

Stimulation of Prostate Cancer Cellular Proliferation and Invasion by the Androgen Receptor Co-Activator ARA70β

Stimulation of Prostate Cancer Cellular Proliferation and Invasion by the Androgen Receptor Co-Activator ARA70β

Targeted therapy of cancer: new roles for pathologists—prostate cancer

Mechanisms of androgen receptor activation in advanced prostate cancer: differential co-activator recruitment and gene expression

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