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

2003 ◽  
Vol 23 (23) ◽  
pp. 8563-8575 ◽  
Author(s):  
Maofu Fu ◽  
Mahadev Rao ◽  
Chenguang Wang ◽  
Toshiyuki Sakamaki ◽  
Jian Wang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Transcription Factor ◽  
Androgen Receptor ◽  
Hdac Inhibitors ◽  
Growth Control ◽  
Cellular Growth ◽  
Gene Promoters ◽  
P300 Binding

ABSTRACT 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.

scholarly journals Functional mapping of androgen receptor enhancer activity

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Chia-Chi Flora Huang ◽  
Shreyas Lingadahalli ◽  
Tunc Morova ◽  
Dogancan Ozturan ◽  
Eugene Hu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Binding Sites ◽  
Gene Promoters ◽  
Strongly Correlated ◽  
Enhancer Activity ◽  
Drive Gene Expression ◽  
In Vitro Cell Lines ◽  
Drive Gene

Abstract Background Androgen receptor (AR) is critical to the initiation, growth, and progression of prostate cancer. Once activated, the AR binds to cis-regulatory enhancer elements on DNA that drive gene expression. Yet, there are 10–100× more binding sites than differentially expressed genes. It is unclear how or if these excess binding sites impact gene transcription. Results To characterize the regulatory logic of AR-mediated transcription, we generated a locus-specific map of enhancer activity by functionally testing all common clinical AR binding sites with Self-Transcribing Active Regulatory Regions sequencing (STARRseq). Only 7% of AR binding sites displayed androgen-dependent enhancer activity. Instead, the vast majority of AR binding sites were either inactive or constitutively active enhancers. These annotations strongly correlated with enhancer-associated features of both in vitro cell lines and clinical prostate cancer samples. Evaluating the effect of each enhancer class on transcription, we found that AR-regulated enhancers frequently interact with promoters and form central chromosomal loops that are required for transcription. Somatic mutations of these critical AR-regulated enhancers often impact enhancer activity. Conclusions Using a functional map of AR enhancer activity, we demonstrated that AR-regulated enhancers act as a regulatory hub that increases interactions with other AR binding sites and gene promoters.

scholarly journals Interleukin-6 stimulation of growth of prostate cancer in vitro and in vivo through activation of the androgen receptor

2009 ◽  
Vol 16 (1) ◽  
pp. 155-169 ◽  
Author(s):  
Kamilla Malinowska ◽  
Hannes Neuwirt ◽  
Ilaria T Cavarretta ◽  
Jasmin Bektic ◽  
Hannes Steiner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Interleukin 6 ◽  
Tumour Progression ◽  
Receptor Activity ◽  
Mitogen Activated Protein Kinase ◽  
Androgen Receptor Activity ◽  
Stimulation Of

It is hypothesized that ligand-independent activation of the androgen receptor is one of the mechanisms implicated in tumour progression. However, supportive evidence is limited to the effect of HER-2/neu that stimulates prostate cancer progression through activation of the androgen receptor. In the present study, we have asked whether the proinflammatory cytokine interleukin-6 (IL-6), which is known to stimulate androgen receptor activity and expression of its downstream target genes, may also induce growth of androgen-sensitive cells. We have found that IL-6 differentially regulates proliferation of LAPC-4 and MDA PCa 2b cells. In MDA PCa 2b cells, growth stimulation by IL-6 was reversed by administration of either the non-steroidal anti-androgen bicalutamide or the inhibitor of the mitogen-activated protein kinase pathway PD98059. Neither cell line was found to express endogenous IL-6. Interestingly, the treatment of those prostate cancer cells did not increase phosphorylation of STAT3. The effect of IL-6 on stimulation of androgen receptor activity in MDA PCa 2b cells was lower than that of androgen, comparable with findings reported by other researchers. However, growth of MDA PCa 2b xenografts in castrated animals treated with IL-6 was similar to that in non-castrated animals. In addition, bicalutamide showed an inhibitory effect on IL-6-regulated growth in vivo. Taken together, data in the present study demonstrate that IL-6 may cause growth of androgen receptor-positive tumours in vitro and in vivo through activation of the androgen receptor.

scholarly journals TRIM59 is Suppressed by Androgen Receptor and Acts to Promote Lineage Plasticity and Neuroendocrine Differentiation in Prostate Cancer

2021 ◽  
Author(s):  
Liancheng Fan ◽  
Yiming Gong ◽  
Yuman He ◽  
Wei-Qiang Gao ◽  
Baijun Dong ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Molecular Mechanisms ◽  
Neuroendocrine Differentiation ◽  
Tumor Model ◽  
Strongly Correlated ◽  
Neuroendocrine Prostate Cancer ◽  
In Vitro Effects

Abstract Background: The incidence of treatment-induced neuroendocrine prostate cancer (t-NEPC) has been greatly increasing after the usage of second-generation androgen receptor (AR) pathway inhibitors (ARPIs). Neuroendocrine differentiation (NED) is closely associated with ARPI treatment failure and poor prognosis in prostate cancer (PCa) patients. However, the molecular mechanisms of NED are not fully understood. Methods: TRIM59 expression was evaluated in PCa samples from patients at first diagnosis or at relapse stage post ARPI treatment by immunohistochemistry; in vitro effects of TRIM59 were determined by cell proliferation, sphere formation and cell migration assays; while in vivo analysis was performed using subcutaneous tumor model. Western blot, qPCR assay, dual luciferase assessment, chromatin immunoprecipitation and RNA sequencing were applied for mechanistic exploration.Results: Here we report that upregulation of TRIM59, a TRIM family protein, is strongly correlated with ARPI treatment mediated NED and shorter patient survival in PCas. AR binds to TRIM59 promoter and represses its transcription. ARPI treatment leads to a reversal of repressive epigenetic modifications on TRIM59 gene and the transcriptional restraint on TRIM59 by AR. Upregulated TRIM59 then drives the NED of PCa by enhancing the degradation of RB1 and P53 and upregulating downstream lineage plasticity-promoting transcription factor SOX2. Conclusion: Altogether, TRIM59 is negatively regulated by AR and acts as a key driver for NED in PCas. Our study provides a novel prognostic marker for PCas and shed new light on the molecular pathogenesis of t-NEPC, a deadly variant of PCa.

scholarly journals Huaier Extract Inhibits Prostate Cancer Growth via Targeting AR/AR-V7 Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhengfang Liu ◽  
Cheng Liu ◽  
Keqiang Yan ◽  
Jikai Liu ◽  
Zhiqing Fang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Mrna Levels ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Specific Protease ◽  
Hormone Sensitive

The androgen receptor (AR) plays a pivotal role in prostatic carcinogenesis, and it also affects the transition from hormone sensitive prostate cancer (HSPC) to castration-resistant prostate cancer (CRPC). Particularly, the persistent activation of the androgen receptor and the appearance of androgen receptor splicing variant 7 (AR-V7), could partly explain the failure of androgen deprivation therapy (ADT). In the present study, we reported that huaier extract, derived from officinal fungi, has potent antiproliferative effects in both HSPC and CRPC cells. Mechanistically, huaier extract downregulated both full length AR (AR-FL) and AR-V7 mRNA levels via targeting the SET and MYND domain-containing protein 3 (SMYD3) signaling pathway. Huaier extract also enhanced proteasome-mediated protein degradation of AR-FL and AR-V7 by downregulating proteasome-associated deubiquitinase ubiquitin-specific protease 14 (USP14). Furthermore, huaier extract inhibited AR-FL/AR-V7 transcriptional activity and their nuclear translocation. More importantly, our data demonstrated that huaier extract could re-sensitize enzalutamide-resistant prostate cancer cells to enzalutamide treatment in vitro and in vivo models. Our work revealed that huaier extract could be effective for treatment of prostate cancer either as monotherapy or in combination with enzalutamide.

Androgen-dependent regulation of Her-2/neu in prostate cancer cells

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 10099-10099
Author(s):  
R. Berger ◽  
D. I. Lin ◽  
M. Nieto ◽  
S. Signoretti ◽  
W. C. Hahn ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Cancer Cells ◽  
Cancer Cell Line ◽  
Prostate Cancer Cell Line ◽  
Prostate Cancer Cells ◽  
In Vivo Experiments ◽  
Her 2

10099 Background: The mechanisms underlying the progression of prostate cancer to androgen independence remain poorly understood. Overexpression of Her-2/neu (c-ErbB2) activates the androgen receptor pathway and confers a survival and growth advantage to prostate cancer cells in an androgen-deficient milieu. Methods: Androgen-sensitive prostate cancer cell line LNCaP was used as a model system in vitro and in vivo. Experiments in mice were undertaken by injecting cells orthotopically into the ventral lobe of the mice prostate. Results: Here, we report that androgen receptor (AR) and Her-2/neu reciprocally regulate each other in LNCaP human prostate cancer cells. Absence of androgens, AR blockade with Casodex (bicalutamide) or suppression of AR with RNAi induced Her-2/neu protein expression and phosphorylation in vitro and in vivo. Similarly, suppression of Her-2-neu expression resulted in AR upregulation. In contrast, upon re-administration of androgens, Her-2/neu mRNA, protein and phosphorylation levels decreased linearly with increasing concentrations of androgens as LNCaP cells re-entered the cell cycle. Conclusions: Thus, induction and activation of Her-2/neu occurs in an androgen-depleted environment or as a result of AR inactivation, promoting androgen-independent survival of prostate cancer cells. No significant financial relationships to disclose.

ODM-204: A novel dual inhibitor of CYP17A1 and androgen receptor for the treatment of castration-resistant prostate cancer—Preclinical data.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 221-221
Author(s):  
Riikka Oksala ◽  
Anu Moilanen ◽  
Reetta Riikonen ◽  
Petteri Rummakko ◽  
Riikka Huhtaniemi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Nuclear Translocation ◽  
Leuprolide Acetate ◽  
Male Rats ◽  
Castration Resistant Prostate Cancer ◽  
Dual Inhibitor ◽  
Castration Resistant

221 Background: Castration-resistant prostate cancer (CRPC) is characterized by high androgen receptor (AR) expression and persistent activation of AR signaling axis by residual tissue/tumor androgens. Targeting AR and androgen biosynthesis together may be more effective than either alone. ODM-204 is a novel, non-steroidal dual inhibitor of CYP17A1 and AR, which has shown promising results in preclinical studies. Methods: The binding affinity of ODM-204 to wild type AR was determined in rat prostate cytosolic lysates. The potency and functional activity of ODM-204 to human AR were demonstrated in cells stably transfected with the full-length AR and androgen-responsive reporter gene constructs. In addition, assays for AR nuclear translocation and the transactivation of human AR mutants T877A, W741L, and F876L were conducted. The effects of ODM-204 on the growth of androgen-dependent VCaP and LNCaP cells in vitro and subcutaneously grafted VCaP cells in vivo with the oral dose of 50 mg/kg/day were studied. The inhibition of CYP17A1 by ODM-204 was studied in vitro by using human and rat testicular microsomes and a human adrenal cortex cell line, and in vivo in male rats coadministered with luteinizing hormone releasing hormone agonist leuprolide acetate to mimic clinical situation. Results: ODM-204 is a potent inhibitor of both AR and CYP17A1. It binds to AR with a high affinity (Ki=47 nM) and selectivity and has a high potency towards CYP17A1 (IC50=22 nM). In addition, ODM-204 inhibited testosterone-mediated nuclear translocation of AR and the mutant ARs (IC50 values for AR(T877A), AR(W741L), and AR(F876L) were 95, 277, and 6 nM, respectively), and suppressed androgen-induced cell proliferation of LNCaP (IC50=170 nM) and VCaP (IC50=280 nM) cells. In a VCaP xenograft model, ODM-204 showed significant antitumor activity (tumor growth inhibition=66%). In rats, inhibitory effects of leuprolide acetate on testosterone production and androgen-sensitive organ weights were potentiated by ODM-204. Conclusions: ODM-204 is a promising new dual CYP17A1 and AR inhibitor for the treatment of CRPC. Clinical trials in patients with mCRPC will be started in early 2015.

ARV-330: Androgen receptor PROTAC degrader for prostate cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 267-267 ◽  
Author(s):  
Taavi K Neklesa ◽  
Meizhong Jin ◽  
Andrew P Crew ◽  
AnnMarie K Rossi ◽  
Ryan R Willard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Therapeutic Effects ◽  
Preclinical Development ◽  
Protein Levels ◽  
Novel Approach ◽  
Subsequent Degradation ◽  
20 Nm

267 Background: The transition from localized prostate cancer to metastatic disease often involves modulation of the Androgen Receptor (AR). During the disease progression, patients progressing on enzalutamide or abiraterone therapy exhibit amplified AR, increased intra-tumoral androgen production or AR mutations leading to promiscuity to other ligands. Therefore, AR is still the principal driver of the disease. Methods: A novel approach to block AR signaling is to specifically target AR for degradation. To this end, we have developed the PROteolysis TArgeting Chimera (PROTAC) technology that employs hetero-bifunctional small molecules that simultaneously bind VHL E3 ubiquitin ligase and a target of interest (e.g. AR). Due to induced proximity between VHL and AR, an AR PROTAC leads to ubiquitination and subsequent degradation of AR. Results: Our lead AR PROTAC, ARV-330, degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentrations (DC50) < 1nM. AR degradation suppresses the AR-target gene PSA expression, inhibits proliferation, and induces potent apoptosis in VCaP cells with maximal apoptosis observed at 20 nM. While enzalutamide loses its activity in the presence of > 0.5 nM R1881, ARV-330 maintains its activity. In cells containing the ARF876L mutation, enzalutamide is an agonist; however, ARV-330 remains effective. In fact, ARV-330 is able to degrade all clinically relevant AR mutations. ARV-330 exhibits good pharmacokinetic properties, with t1/2 values of several hours and bioavailability of > 80% after sc injection. Treatment of mice with ARV-330, at doses ranging from 0.3 to 10 mg/kg, results in reduction of AR protein levels. The in vitro potency translates into in vivo efficacy, as ARV-330 demonstrates prostate involution in intact mice. In castrated mice implanted with VCaP tumors, ARV-330 shows robust reduction of plasma PSA and blockade of tumor growth. Conclusions: In summary, the AR PROTAC ARV-330 removes AR from prostate cancer cells in a potent manner and produces therapeutic effects as a result. This cellular efficacy has translated into biomarker activity and efficacy in animal models, and ARV-330 is now in preclinical development.

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