Inhibition of Histone Deacetylase induces miR-320-mediated Androgen Receptor Suppression in Prostate Cancer
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE69489 | GEO | 2016/06/01
SECONDARY ACCESSION(S): PRJNA285700
REPOSITORIES: GEO
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below. Refer to individual Series
2016-06-01 | E-GEOD-69489 | biostudies-arrayexpress
Project description:Inhibition of Histone Deacetylase induces miR-320-mediated Androgen Receptor Suppression in Prostate Cancer
| PRJNA285700 | ENA
Project description:Androgen receptor (AR)-null prostate tumors have been observed in 11-24% of patients. Histone deacetylases (HDACs) are overexpressed in prostate tumors. Therefore, HDAC inhibitors (Jazz90 and Jazz167) were examined in AR-null prostate cancer cell lines (PC3 and DU145). Both Jazz90 and Jazz167 inhibited the growth of PC3 and DU145 cells. Jazz90 and Jazz167 were more active in PC3 cells and DU145 cells in comparison to normal prostate cells (PNT1A) and showed a 2.45- and 1.30-fold selectivity and higher cytotoxicity toward DU145 cells, respectively. Jazz90 and Jazz167 reduced HDAC activity by ~60% at 50 nM in PC3 lysates. At 4 μM, Jazz90 and Jazz167 increased acetylation in PC3 cells by 6- to 8-fold. Flow cytometry studies on the cell phase distribution demonstrated that Jazz90 causes a G0/G1 arrest in AR-null cells, whereas Jazz167 leads to a G0/G1 arrest in DU145 cells. However, apoptosis only occurred at a maximum of 7% of the total cell population following compound treatments in PC3 and DU145 cells. There was a reduction in cyclin D1 and no significant changes in bcl-2 in DU145 and PC3 cells. Overall, the results showed that Jazz90 and Jazz167 function as cytostatic HDAC inhibitors in AR-null prostate cancer cells.
| S-EPMC7912319 | biostudies-literature
Project description:High consumption of cruciferous vegetables is associated with a reduced risk of prostate cancer in epidemiological studies. There is preliminary evidence that sulforaphane, derived from glucoraphanin found in a number of crucifers, may prevent and induce regression of prostate cancer and other malignancies in preclinical models, but the mechanisms that may explain these effects are not fully defined. Recent reports show that sulforaphane may impair prostate cancer growth through inhibition of histone deacetylases, which are up-regulated in cancer. Indeed, one of these enzymes, histone deacetylase 6 (HDAC6), influences the acetylation state of a key androgen receptor (AR) chaperone, HSP90. AR is the central signaling pathway in prostate cancer, and its inhibition is used for both prevention and treatment of this disease. However, it is not known whether the effects of sulforaphane involve suppression of AR. We hypothesized that sulforaphane treatment would lead to hyperacetylation of HSP90 and that this would destabilize AR and attenuate AR signaling. We confirmed this by demonstrating that sulforaphane enhances HSP90 acetylation, thereby inhibiting its association with AR. Moreover, AR is subsequently degraded in the proteasome, which leads to reduced AR target gene expression and reduced AR occupancy at its target genes. Finally, sulforaphane inhibits HDAC6 deacetylase activity, and the effects of sulforaphane on AR protein are abrogated by overexpression of HDAC6 and mimicked by HDAC6 siRNA. The inactivation by sulforaphane of HDAC6-mediated HSP90 deacetylation and consequent attenuation of AR signaling represents a newly defined mechanism that may help explain this agent's effects in prostate cancer.
| S-EPMC2757849 | biostudies-other
Project description:The suppression of androgen receptor (AR) expression exacerbates the migration potential of prostate cancer. This study identified a previously unrecognized regulation of the AR-controlled pathway that promotes migration potential in prostate cancer cells. Prostate cancer cells that pass through a transwell membrane (mig cells) have a higher migration potential with a decreased AR expression than parental cells. In this study, we aimed to elucidate the mechanism of migration enhancement associated with the suppression of AR signaling. Expression of C-C motif ligand 20 (CCL20) is upregulated in mig cells, unlike in the parental cells. Knockdown of AR with small interfering RNA (siAR) in LNCaP and C4-2B cells increased CCL20 secretion and enhanced the migration of cancer cells. Mig cells, CCL20-treated cells, and siAR cells promoted cell migration with an enhancement of AKT phosphorylation and Snail expression, while the addition of a C-C chemokine receptor 6 (CCR6, the specific receptor of CCL20) inhibitor, anti-CCL20 antibody, and AKT inhibitor suppressed the activation of AKT and Snail. With 59 samples of prostate cancer tissue, CCL20 secretion was profuse in metastatic cases despite low AR expression levels. Snail expression was associated with the expression of CCL20 and CCR6. A xenograft study showed that the anti-CCL20 antibody significantly inhibited Snail expression, thereby suggesting a new therapeutic approach for castration-resistant prostate cancer with the inhibition of the axis between CCL20 and CCR6.
| S-EPMC10067408 | biostudies-literature
Project description:microRNAs (miRNAs) are small non-coding RNAs that regulate cellular processes by fine-tuning the levels of their target mRNAs. However, the regulatory elements determining cellular miRNA levels are not well studied. Previously, we had described an altered miRNA signature in the skeletal muscle of db/db mice. Here, we sought to explore the role of epigenetic mechanisms in altering these miRNAs. We show that histone deacetylase (HDAC) protein levels and activity are upregulated in the skeletal muscle of diabetic mice. In C2C12 cells, HDAC inhibition using suberoylanilide hydroxamic acid (SAHA) altered the levels of 24 miRNAs: 15 were downregulated and 9 were upregulated. miR-449a, an intronic miRNA localized within the Cdc20b gene, while being downregulated in the skeletal muscle of diabetic mice, was the most highly upregulated during HDAC inhibition. The host gene, Cdc20b, was also significantly upregulated during HDAC inhibition. Bioinformatics analyses identified a common promoter for both Cdc20b and miR-449a that harbors significant histone acetylation marks, suggesting the possibility of regulation by histone acetylation-deacetylation. These observations suggest an inverse correlation between miR-449a levels and HDAC activity, in both SAHA-treated skeletal muscle cells and db/db mice skeletal muscle. Further, in SAHA-treated C2C12 cells, we observed augmented occupancy of acetylated histones on the Cdc20b/miR-449a promoter, which possibly promotes their upregulation. In vivo injection of SAHA to db/db mice significantly restored skeletal muscle miR-449a levels. Our results provide insights into the potential regulatory role of epigenetic histone acetylation of the miR-449a promoter that may regulate its expression in the diabetic skeletal muscle.
| S-EPMC4990227 | biostudies-literature
Project description:Metastatic prostate cancer is initially treated with androgen ablation therapy, which causes regression of androgen-dependent tumors. However, these tumors eventually relapse resulting in recurrent castration-resistant prostate cancer (CRPC). Currently, there is no effective therapy for CRPC and the molecular mechanisms that lead to the development of CRPC are not well understood. Here, we evaluated the hypothesis that combined inhibition of Hedgehog (Hh) and androgen receptor (AR) signaling will synergistically attenuate the growth of CRPC in vitro and in vivo. Androgen deprivation induced full-length androgen receptor protein levels in CRPC cells, but decreased its nuclear localization and transcriptional activity. However, androgen deprivation also increased a truncated form of androgen receptor (lacking ligand-binding domain) that possessed transcriptional activity in CRPC cells. Androgen deprivation also promoted the expression of Hh signaling components in CRPC cells, xenograft tumors, and the prostate glands of castrated mice. Importantly, although inhibition of either Hh or androgen receptor signaling alone was only moderately effective in blocking CRPC cell growth, combination of an Hh pathway inhibitor and a noncompetitive androgen receptor inhibitor synergistically suppressed the growth of CRPC cells in vitro and in vivo. Finally, noncompetitive inhibition of androgen receptor, but not competitive inhibition, was effective at limiting the activity of truncated androgen receptor leading to the inhibition of CRPC.Combined therapy using Hh inhibitors and a non-competitive AR inhibitor may limit CRPC growth.
| S-EPMC3834015 | biostudies-literature
Project description:Recently, it was demonstrated that lineage-committed oligodendrocyte precursor cells (OPCs) can be converted to multipotent neural stem-like cells, capable of generating both neurons and glia after exposure to bone morphogenetic proteins. In an effort to understand and control the developmental plasticity of OPCs, we developed a high-throughput screen to identify novel chemical inducers of OPC reprogramming. Using this system, we discovered that inhibition of histone deacetylase (HDAC) activity in OPCs acts as a priming event in the induction of developmental plasticity, thereby expanding the differentiation potential to include the neuronal lineage. This conversion was found to be mediated, in part, through reactivation of sox2 and was highly reproducible at the clonal level. Further, genome-wide expression analysis demonstrated that HDAC inhibitor treatment activated sox2 and 12 other genes that identify or maintain the neural stem cell state while simultaneously silencing a large group of oligodendrocyte lineage-specific genes. This series of experiments demonstrates that global histone acetylation, induced by HDAC inhibition, can partially reverse the lineage restriction of OPCs, thereby inducing developmental plasticity.
| S-EPMC1986599 | biostudies-literature
Project description:Androgen receptor (AR) is a ligand-dependent transcription factor, which plays a significant role in prostate carcinogenesis. Blockade of AR and its ligand, androgen is the basis for the treatment of prostate cancer (PCa). Nevertheless, a modest increase in the critical levels of AR mRNA and corresponding protein is sufficient for the development of resistance to antiandrogen therapy. A strategy to further downregulate AR mRNA and protein expression in combination with antiandrogen therapy may prevent or delay the development of androgen-independent PCa. Recent studies show that microRNAs (miRNAs) perform tumor suppressor functions in various cancers. In this study, we demonstrate that the overexpression of miR 488* downregulates the transcriptional activity of AR and inhibits the endogenous AR protein production in both androgen-dependent and androgen-independent PCa cells. In addition, miR 488* blocks the proliferation and enhances the apoptosis of PCa cells. Our data indicate that miR 488* targets AR and is a potential modulator of AR mediated signaling. Our findings provide insight for utilizing miRNAs as novel therapeutics to target AR in PCa.
| S-EPMC3839820 | biostudies-literature
Project description:Exploitation of DNA repair defects has enabled major advances in treating specific cancers. Recent work discovered that the oncometabolite 2-hydroxyglutarate (2-HG), produced by neomorphic isocitrate dehydrogenase 1/2 (IDH1/2) mutations, confers a homology-directed repair (HDR) defect through 2-HG-induced histone hypermethylation masking HDR signaling. Here, we report that IDH1-mutant cancer cells are profoundly sensitive to the histone deacetylase inhibitor (HDACi) vorinostat, by further suppressing the residual HDR in 2-HG-producing cells. Vorinostat downregulates repair factors BRCA1 and RAD51 via disrupted E2F-factor regulation, causing increased DNA double-strand breaks, reduced DNA repair factor foci, and functional HDR deficiency even beyond 2-HG's effects. This results in greater cell death of IDH1-mutant cells and confers synergy with radiation and PARPi, both against cells in culture and patient-derived tumor xenografts. Our work identifies HDACi's utility against IDH1-mutant cancers, and presents IDH1/2 mutations as potential biomarkers to guide trials testing HDACi in gliomas and other malignancies. IMPLICATIONS: IDH1-mutant cells show profound vulnerability to HDACi treatment, alone and with PARPi and radiation, via HDR suppression, presenting IDH1/2 mutations as biomarkers for HDACi use in gliomas and other malignancies.
| S-EPMC8642278 | biostudies-literature