Rapid Androgen-Responsive Proteome Is Involved in Prostate Cancer Progression.
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ABSTRACT:
SUBMITTER: Kim JK
PROVIDER: S-EPMC8698566 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Gene fusion between TMPRSS2 promoter and the ERG proto-oncogene is a major genomic alteration found in over half of prostate cancers (CaP), which leads to aberrant androgen dependent ERG expression. Despite extensive analysis for the biological functions of ERG in CaP, there is no systematic evaluation of the ERG responsive proteome (ERP). ERP has the potential to define new biomarkers and therapeutic targets for prostate tumors stratified by ERG expression.Global proteome analysis was performed by using ERG (+) and ERG (-) CaP cells isolated by ERG immunohistochemistry defined laser capture microdissection and by using TMPRSS2-ERG positive VCaP cells treated with ERG and control siRNA.We identified 1,196 and 2,190 unique proteins stratified by ERG status from prostate tumors and VCaP cells, respectively. Comparative analysis of these two proteomes identified 330 concordantly regulated proteins characterizing enrichment of pathways modulating cytoskeletal and actin reorganization, cell migration, protein biosynthesis, and proteasome and ER-associated protein degradation. ERPs unique for ERG (+) tumors reveal enrichment for cell growth and survival pathways while proteasome and redox function pathways were enriched in ERPs unique for ERG (-) tumors. Meta-analysis of ERPs against CaP gene expression data revealed that Myosin VI and Monoamine oxidase A were positively and negatively correlated to ERG expression, respectively.This study delineates the global proteome for prostate tumors stratified by ERG expression status. The ERP data confirm the functions of ERG in inhibiting cell differentiation and activating cell growth, and identify potentially novel biomarkers and therapeutic targets.
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Project description:High-throughput techniques have identified numerous antisense (AS) transcripts and long non-coding RNAs (ncRNAs). However, their significance in cancer biology remains largely unknown. Here, we report an androgen-responsive long ncRNA, CTBP1-AS, located in the AS region of C-terminal binding protein 1 (CTBP1), which is a corepressor for androgen receptor. CTBP1-AS is predominantly localized in the nucleus and its expression is generally upregulated in prostate cancer. CTBP1-AS promotes both hormone-dependent and castration-resistant tumour growth. Mechanistically, CTBP1-AS directly represses CTBP1 expression by recruiting the RNA-binding transcriptional repressor PSF together with histone deacetylases. CTBP1-AS also exhibits global androgen-dependent functions by inhibiting tumour-suppressor genes via the PSF-dependent mechanism thus promoting cell cycle progression. Our findings provide new insights into the functions of ncRNAs that directly contribute to prostate cancer progression.
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Project description:Mechanisms mediating androgen receptor (AR) reactivation in prostate cancer that progresses after castration (castration-resistant prostate cancer; CRPC) and subsequent treatment with abiraterone (CYP17A1 inhibitor that further suppresses androgen synthesis) remain unclear.Prostate cancer xenografts were examined to identify mechanism of progression after castration and abiraterone.AR reactivation in abiraterone-resistant VCaP xenografts was not associated with restoration of intratumoral androgens or alterations in AR coregulators. In contrast, mRNA encoding full-length AR (AR-FL) and a constitutively active splice variant (AR-V7) were increased compared with xenografts before castration, with an increase in AR-V7 relative to AR-FL. This shift toward AR-V7 was due to a feedback mechanism whereby the androgen-liganded AR stimulates expression of proteins that suppress generation of AR-V7 relative to AR-FL transcripts. However, despite the increases in AR-V7 mRNA, it remained a minor transcript (<1%) relative to AR-FL in resistant VCaP xenografts and CRPC clinical samples. AR-V7 protein expression was similarly low relative to AR-FL in castration-resistant VCaP xenografts and androgen-deprived VCaP cells, but the weak basal AR activity in these latter cells was further repressed by AR-V7 siRNA.AR-V7 at these low levels is not adequate to restore AR activity, but its rapid induction after androgen deprivation allows tumors to retain basal AR activity that may be needed for survival until more potent mechanisms emerge to activate AR. Agents targeting AR splice variants may be most effective when used very early in conjunction with therapies targeting the AR ligand-binding domain.
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Project description:Progression of prostate cancer (CaP) relies on androgen receptor (AR) signaling, but AR-dependent events that underlie the lethal phenotype remain unknown. Recently, an indirect mechanism of androgen action in which effects of AR on CaP cells are mediated by Serum Response Factor (SRF) has been identified. This is the first mode of androgen action to be associated with aggressive CaP and disease recurrence. The manner in which androgen-responsive SRF activity controls aggressive CaP cell behavior is unknown. Here, the contribution of two representative SRF effector genes that are underexpressed, calponin 2 (CNN2), or overexpressed, sidekick-homolog 1 (SDK1), in clinical CaP specimens is studied. AR- and SRF- dependency of CNN2 and SDK1 expression was verified using synthetic and natural androgens, antiandrogens, and small interfering RNAs targeting AR or SRF, and evaluating the kinetics of androgen induction and SRF binding to endogenously and exogenously expressed regulatory gene regions in AR-positive CaP model systems that mimic the transition from androgen-stimulated to castration-recurrent disease. Small interfering RNA-mediated deregulation of CNN2 or SDK1 expression did not affect CaP cell proliferation or apoptosis but had marked effects on CaP cell morphology and actin cytoskeleton organization. Loss of CNN2 induced cellular protrusions and increased CaP cell migration, whereas silencing of SDK1 led to cell rounding and blunted CaP cell migration. Changes in cell migration did not involve epithelial-mesenchymal transition but correlated with altered ?1-integrin expression. Taken together, individual androgen-responsive SRF target genes affect CaP cell behavior by modulating cell migration, which may have implications for therapeutic intervention downstream of AR and SRF.
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Project description:BPTF associated protein of 18 kDa (BAP18) has been reported as a component of MLL1-WDR5 complex. However, BAP18 is an uncharacterized protein. The detailed biological functions of BAP18 and underlying mechanisms have not been defined. Androgen receptor (AR), a member of transcription factor, plays an essential role in prostate cancer (PCa) and castration-resistant prostate cancer (CRPC) progression. Here, we demonstrate that BAP18 is identified as a coactivator of AR in Drosophilar experimental system and mammalian cells. BAP18 facilitates the recruitment of MLL1 subcomplex and AR to androgen-response element (ARE) of AR target genes, subsequently increasing histone H3K4 trimethylation and H4K16 acetylation. Knockdown of BAP18 attenuates cell growth and proliferation of PCa cells. Moreover, BAP18 depletion results in inhibition of xenograft tumor growth in mice even under androgen-depletion conditions. In addition, our data show that BAP18 expression in clinical PCa samples is higher than that in benign prostatic hyperplasia (BPH). Our data suggest that BAP18 as an epigenetic modifier regulates AR-induced transactivation and the function of BAP18 might be targeted in human PCa to promote tumor growth and progression to castration-resistance.
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Project description:Castration resistance is a major obstacle to hormonal therapy for prostate cancer patients. Although androgen independence of prostate cancer growth is a known contributing factor to endocrine resistance, the mechanism of androgen receptor deregulation in endocrine resistance is still poorly understood. Herein, the CAMK2N1 was shown to contribute to the human prostate cancer cell growth and survival through AR-dependent signaling. Reduced expression of CAMK2N1 was correlated to recurrence-free survival of prostate cancer patients with high levels of AR expression in their tumor. CAMK2N1 and AR signaling form an auto-regulatory negative feedback loop: CAMK2N1 expression was down-regulated by AR activation; while CAMK2N1 inhibited AR expression and transactivation through CAMKII and AKT pathways. Knockdown of CAMK2N1 in prostate cancer cells alleviated Casodex inhibition of cell growth, while re-expression of CAMK2N1 in castration-resistant cells sensitized the cells to Casodex treatment. Taken together, our findings suggest that CAMK2N1 plays a tumor suppressive role and serves as a crucial determinant of the resistance of prostate cancer to endocrine therapies.
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Project description:Tocopherylquinone (TQ), the oxidation product of alpha-tocopherol (AT), is a bioactive molecule with distinct properties from AT. In this study, AT and TQ are investigated for their comparative effects on growth and androgenic activity in prostate cancer cells. TQ potently inhibited the growth of androgen-responsive prostate cancer cell lines (e.g., LAPC4 and LNCaP cells), whereas the growth of androgen-independent prostate cancer cells (e.g., DU145 cells) was not affected by TQ. Due to the growth inhibitory effects induced by TQ on androgen-responsive cells, the anti-androgenic properties of TQ were examined. TQ inhibited the androgen-induced activation of an androgen-responsive reporter and inhibited the release of prostate specific antigen from LNCaP cells. TQ pretreatment was also found to inhibit AR activation as measured using the Multifunctional Androgen Receptor Screening assay. Furthermore, TQ decreased androgen-responsive gene expression, including TM4SF1, KLK2, and PSA over 5-fold, whereas AT did not affect the expression of androgen-responsive genes. Of importance, the antiandrogenic effects of TQ on prostate cancer cells were found to result from androgen receptor protein down-regulation produced by TQ that was not observed with AT treatment. Moreover, none of the androgenic endpoints assessed were affected by AT. The down-regulation of androgen receptor protein by TQ was abrogated by co-treatment with antioxidants. Overall, the biological actions of TQ were found to be distinct from AT, where TQ was found to be a potent inhibitor of cell growth and androgenic activity in androgen-responsive prostate cancer cells.
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Project description:UnlabelledThe androgen receptor (AR) is the dominant growth factor in prostate cancer (PCa). Therefore, understanding how ARs regulate the human transcriptome is of paramount importance. The early effects of castration on human PCa have not previously been studied 27 patients medically castrated with degarelix 7 d before radical prostatectomy. We used mass spectrometry, immunohistochemistry, and gene expression array (validated by reverse transcription-polymerase chain reaction) to compare resected tumour with matched, controlled, untreated PCa tissue. All patients had levels of serum androgen, with reduced levels of intraprostatic androgen at prostatectomy. We observed differential expression of known androgen-regulated genes (TMPRSS2, KLK3, CAMKK2, FKBP5). We identified 749 genes downregulated and 908 genes upregulated following castration. AR regulation of ?-methylacyl-CoA racemase expression and three other genes (FAM129A, RAB27A, and KIAA0101) was confirmed. Upregulation of oestrogen receptor 1 (ESR1) expression was observed in malignant epithelia and was associated with differential expression of ESR1-regulated genes and correlated with proliferation (Ki-67 expression).Patient summaryThis first-in-man study defines the rapid gene expression changes taking place in prostate cancer (PCa) following castration. Expression levels of the genes that the androgen receptor regulates are predictive of treatment outcome. Upregulation of oestrogen receptor 1 is a mechanism by which PCa cells may survive despite castration.
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