GRK2 enforces androgen receptor dependence in the prostate and prostate tumors (original) (raw)
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GRK3 is essential for metastatic cells and promotes prostate tumor progression
Proceedings of the National Academy of Sciences, 2014
Significance Although the majority of cancer-related deaths are consequences of metastatic dissemination, the molecular and cellular forces that drive tumor cell dispersion are still poorly understood. To help identify new regulators that play critical roles in these processes, we screened for human kinases that are important for continued survival of metastatic cells. One kinase identified from these screens, the G-protein–coupled receptor kinase 3 (GRK3; or β-adrenergic receptor kinase 2), was found to have a key role in promoting prostate tumor growth and metastasis in mouse models through enhancing angiogenesis. Notably, GRK3 is overexpressed in human prostate metastatic tumors. Further studies on GRK3 and its pathways promise to expand our knowledge of cancer metastasis and also yield new cancer therapeutic targets.
International Journal of Cancer, 2011
G-protein coupled receptor (GPCR)-stimulated androgen-independent activation of androgen receptor (AR) contributes to acquisition of a hormone-refractory phenotype by prostate cancer. We previously reported that regulator of G-protein signaling (RGS) 2, an inhibitor of GPCRs, inhibits androgen-independent AR activation. 1 Here, we show reduced RGS2 protein expression in human prostate cancer specimens compared to adjacent normal or hyperplastic tissue. Methylation-specific PCR analysis and bisulfite sequencing indicated that methylation of the CpG island in the RGS2 gene promoter correlated with RGS2 down-regulation in prostate cancer. In vitro methylation of this promoter suppressed reporter gene expression in transient transfection studies, whereas reversal of this promoter methylation with 5-aza-2′-deoxycytidine (5-Aza-dC) induced RGS2 re-expression in androgen-independent prostate cancer cells and inhibited their growth under androgen-deficient conditions. Interestingly, the inhibitory effect of 5-Aza-dC was significantly reduced by an RGS2-targeted short hairpin RNA, indicating that re-expressed RGS2 contributed to this growth inhibition. Restoration of RGS2 levels by ectopic expression in androgen-independent prostate cancer cells suppressed growth of xenografts in castrated mice. Thus, RGS2 promoter hypermethylation represses its expression and unmasks a latent pathway for AR transactivation in prostate cancer cells. Targeting this reversible process may provide a new strategy for suppressing prostate cancer progression by reestablishing its androgen-sensitivity.
Cancer Research, 2006
Androgen receptor (AR) is a ligand-induced transcriptional factor, which plays an important role in the normal development of prostate as well as in the progression of prostate cancer. Numerous coactivators, which associate with AR and function to remodel chromatin and recruit RNA polymerase II to enhance the transcriptional potential of AR, have been identified. Among these coactivators, few are protein kinases. In this study, we describe the characterization of a novel protein kinase, male germ cell-associated kinase (MAK), which serves as a coactivator of AR. We present evidence, which indicates that (a) MAK physically associates with AR (MAK and AR are found to be coprecipitated from cell extracts, colocalized in nucleus, and corecruited to prostate-specific antigen promoter in LNCaP as well as in transfected cells); (b) MAK is able to enhance AR transactivation potential in an androgen-and kinase-dependent manner in several prostate cancer cells and synergize with ACTR/steroid receptor coactivator-3 coactivator; (c) small hairpin RNA (shRNA) knocks down MAK expression resulting in the reduction of AR transactivation ability; (d) MAK-shRNA or kinase-dead mutant, when introduced into LNCaP cells, reduces the growth of the cells; and (e) microarray analysis of LNCaP cells carrying kinase-dead MAK mutant showed a significant impediment of AR signaling, indicating that endogenous MAK plays a general role in AR function in prostate cancer cells and likely to be a general coactivator of AR in prostate tissues. The highly restricted expression of this kinase makes it a potentially useful target for intervention of androgen independence. (Cancer Res 2006; 66(17): 8439-47) Requests for reprints: Hsing-Jien Kung,
Cancer research, 2017
Alterations to the expression and activity of androgen receptor (AR) co-regulators in prostate cancer is an important mechanism driving disease progression and therapy resistance. Using a novel proteomic technique, we identified a new AR co-regulator, the transcription factor Grainyhead-like 2 (GRHL2), and demonstrated its essential role in the oncogenic AR signaling axis. GRHL2 colocalized with AR in prostate tumors and was frequently amplified and upregulated in prostate cancer. Importantly, GRHL2 maintained AR expression in multiple prostate cancer model systems, was required for cell proliferation, enhanced AR's transcriptional activity, and co-located with AR at specific sites on chromatin to regulate genes relevant to disease progression. GRHL2 is itself an AR-regulated gene, creating a positive feedback loop between the two factors. The link between GRHL2 and AR also applied to constitutively active truncated AR variants (ARVs), as GRHL2 interacted with and regulated ARVs...
Oncogene, 2004
The transcriptional activity of the androgen receptor (AR) is regulated by interaction with various coregulators, one of which is b-catenin. Interest in the role of b-catenin in prostate cancer has been stimulated by reports showing that it is aberrantly expressed in the cytoplasm and/or nucleus in up to 38% of hormone-refractory tumours and that overexpression of b-catenin results in activation of AR transcriptional activity. We have examined the effect of depleting endogenous b-catenin on AR activity using Axin and RNA interference. Axin, which promotes b-catenin degradation, inhibited AR transcriptional activity. However, this did not require the b-catenin-binding domain of Axin. Depletion of b-catenin using RNA interference increased, rather than decreased, AR activity, suggesting that endogenous b-catenin is not a transcriptional coactivator for the AR. The glycogen synthase kinase-3 (GSK-3)-binding domain of Axin prevented formation of a GSK-3-AR complex and was both necessary and sufficient for inhibition of AR-dependent transcription. A second GSK-3-binding protein, FRAT, also inhibited AR transcriptional activity, as did the GSK-3 inhibitors SB216763 and SB415286. Finally, inhibition of GSK-3 reduced the growth of AR-expressing prostate cancer cell lines. Our observations suggest a potential new therapeutic application for GSK-3 inhibitors in prostate cancer.
Oncogene, 2006
Hormones acting through G protein-coupled receptors (GPCRs) can cause androgen-independent activation of androgen receptor (AR) in prostate cancer cells. Regulators of G-protein signaling (RGS) proteins, through their GTPase activating protein (GAP) activities, inhibit GPCR-mediated signaling by inactivating G proteins. Here, we identified RGS2 as a gene specifically downregulated in androgen-independent prostate cancer cells. Expression of RGS2, but not other RGS proteins, abolished androgen-independent AR activity in androgenindependent LNCaP cells and CWR22Rv1 cells. In LNCaP cells, RGS2 inhibited G q-coupled GPCR signaling. Expression of exogenous wild-type RGS2, but not its GAP-deficient mutant, significantly reduced AR activation by constitutively activated G q Q209L mutant whereas silencing endogenous RGS2 by siRNA enhanced G q Q209L-stimulated AR activity. RGS2 had no effect on RGS-insensitive G q Q209L/G188S-induced AR activation. Furthermore, extracellular signal-regulated kinase 1/2 (ERK1/2) was found to be involved in RGS2-mediated regulation of androgen-independent AR activity. In addition, RGS2 functioned as a growth suppressor for androgen-independent LNCaP cells whereas androgensensitive LNCaP cells with RGS2 silencing had a growth advantage under steroid-reduced conditions. Finally, RGS2 expression level was significantly decreased in human prostate tumor specimens. Taken together, our results suggest RGS2 as a novel regulator of AR signaling and its repression may be an important step during prostate tumorigenesis and progression.
Kinase modulation of androgen receptor signaling: implications for prostate cancer
Cancer cell & microenvironment, 2015
Androgens and androgen receptors play essential roles in the development and progression of prostate cancer, a disease that claims roughly 28,000 lives annually. In addition to androgen biding, androgen receptor activity can be regulated via several post-translational modifications such as ubiquitination, acetylation, phosphorylation, methylation & SUMO-ylation. Off these modifications, phosphorylation has been the most extensively studied. Modification by phosphorylation can alter androgen receptor localization, protein stability and transcriptional activity, ultimately leading to changes in the biology of cancer cells and cancer progression. Understanding, role of phosphorylated androgen receptor species holds the key to identifying a potential therapeutic drug target for patients with prostate cancer and castrate resistant prostate cancer. Here, we present a brief review of recently discovered protein kinases phosphorylating AR, focusing on the functional role of phosphorylated a...
The EMBO Journal, 2003
In addition to the classical activation by ligands, nuclear receptor activity is also regulated by ligandindependent signalling. Here, we unravel a novel signal transduction pathway that links the RhoA effector protein kinase C-related kinase PRK1 to the transcriptional activation of the androgen receptor (AR). Stimulation of the PRK signalling cascade results in a ligand-dependent superactivation of AR. We show that AR and PRK1 interact both in vivo and in vitro. The transactivation unit 5 (TAU-5) located in the N-terminus of AR suf®ces for activation by PRK1. Thus, TAU-5 de®nes a novel, signal-inducible transactivation domain. Furthermore, PRK1 promotes a functional complex of AR with the co-activator TIF-2. Importantly, PRK signalling also stimulates AR activity in the presence of adrenal androgens, which are still present in prostate tumour patients subjected to testicular androgen ablation therapy. Moreover, PRK1 activates AR even in the presence of the AR antagonist cyproterone acetate that is used in the clinical management of prostate cancer. Since prostate tumours strongly overexpress PRK1, our data support a model in which AR activity is controlled by PRK signalling. Keywords: androgen receptor/nuclear hormone receptor/ prostate cancer/protein kinase C-related kinase/ transcriptional co-activator A novel inducible transactivation domain in the androgen receptor: implications for PRK in prostate cancer
Journal of Biological Chemistry, 2004
Androgens play important roles in the growth of normal prostate and prostate cancer via binding to the androgen receptor (AR). In addition to androgens, AR activity can also be modulated by selective growth factors and/or kinases. Here we report a new kinase signaling pathway by showing that AR transactivation was repressed by wild type glycogen synthase kinase 3 (GSK3) or constitutively active S9A-GSK3 in a dosedependent manner. In contrast, the catalytically inactive kinase mutant GSK3 showed little effect on the AR transactivation. The suppression of AR transactivation by GSK3 was abolished by the GSK3 inhibitor lithium chloride. The in vitro kinase assay showed that GSK3 prefers to phosphorylate the amino terminus of AR that may lead to the suppression of activation function 1 activity located in the NH 2 -terminal region of AR. GSK3 interrupted the interaction between the NH 2 and COOH termini of AR, and overexpression of the constitutively active form of GSK3, S9A-GSK3, reduced the androgen-induced prostate cancer cell growth in stably transfected CWR22R cells. Together, our data demonstrated that GSK3 may function as a repressor to suppress AR-mediated transactivation and cell growth, which may provide a new strategy to modulate the ARmediated prostate cancer growth.