Immune modulation underpins the anti-cancer activity of HDAC inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA664188 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR12663677.fastq.gz | Fastqsanger.gz | |||
| SRR12663677_1.fastq.gz | Fastqsanger.gz | |||
| SRR12663677_2.fastq.gz | Fastqsanger.gz | |||
| SRR12663678.fastq.gz | Fastqsanger.gz | |||
| SRR12663678_1.fastq.gz | Fastqsanger.gz |
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Project description:We have explored at the genome-wide expression level the effects of the novel HDAC inhibitor CXD101. In human CRC cell lines, a diverse set of differentially expressed genes were up- and down-regulated. Functional profiling of the expression data highlighted immune-relevant concepts related to antigen processing and natural killer (NK) cell mediated cytotoxicity. Similar gene profiles were apparent when global gene expression was investigated in murine CT26 cells treated with CXD101, which were also apparent in syngeneic CT26 tumours growing in vivo. The ability of CXD101 to affect immune-relevant gene expression coincided with changes in the tumour micro-environment (TME), especially in the sub-groups of tumour-infiltrating lymphocytes which occurred upon CXD101 treatment. The altered TME reflected synergistic anti-tumour activity apparent when CXD101 was combined with immune oncology (IO) agents, like anti-PD1 and anti-CTLA4.The ability of CXD101 to instate antigen presentation and augment NK activity in the TME, combined with the synergy between HDAC inhibitors and IO agents, provides a powerful rationale for exploring the combination effect in human cancers.
2021-06-30 | GSE158164 | GEO
Project description:Aberrant protein acetylation is strongly linked to tumorigenesis, and modulating acetylation through targeting histone deacetylase (HDAC) with small-molecule inhibitors has been the focus of clinical trials. However, clinical success on solid tumours, such as colorectal cancer (CRC), has been limited, in part because the cancer-relevant mechanisms through which HDAC inhibitors act remain largely unknown. Here, we have explored, at the genome-wide expression level, the effects of a novel HDAC inhibitor CXD101. In human CRC cell lines, a diverse set of differentially expressed genes were up- and downregulated upon CXD101 treatment. Functional profiling of the expression data highlighted immune-relevant concepts related to antigen processing and natural killer cell-mediated cytotoxicity. Similar profiles were apparent when gene expression was investigated in murine colon26 CRC cells treated with CXD101. Significantly, these changes were also apparent in syngeneic colon26 tumours growing in vivo. The ability of CXD101 to affect immune-relevant gene expression coincided with changes in the tumour microenvironment (TME), especially in the subgroups of CD4 and CD8 tumour-infiltrating T lymphocytes. The altered TME reflected enhanced antitumour activity when CXD101 was combined with immune checkpoint inhibitors (ICIs), such as anti-PD-1 and anti-CTLA4. The ability of CXD101 to reinstate immune-relevant gene expression in the TME and act together with ICIs provides a powerful rationale for exploring the combination therapy in human cancers.
| S-EPMC8637571 | biostudies-literature
Project description:Histone deacetylase (HDAC) inhibition has been shown in previous studies to disrupt the synovial sarcoma oncoprotein complex, resulting in apoptosis. To understand the molecular effects of HDAC inhibition, RNA-Seq transcriptome analysis was undertaken in six human synovial sarcoma cell lines. HDAC inhibition induced pathways of cell cycle arrest, neuronal differentiation and response to oxygen-containing species, effects also observed in other cancers treated with this class of drugs. More specific to synovial sarcoma, polycomb-group targets were reactivated including tumor suppressor CDKN2A, and pro-apoptotic transcriptional patterns were induced. Functional analyses revealed that ROS-mediated FOXO activation and pro-apoptotic factors BIK, BIM and BMF were important to apoptosis induction following HDAC-inhibition in synovial sarcoma
| EGAS00001002637 | EGA
Project description:Histone deacetylases (HDACs) regulate gene expression. Inhibition of class I HDACs has been shown to inhibit cancer cell growth. Largazole, a new potent HDAC inhibitor, shows strong antitumor activity, presumably by modulating transcription of cancer relevant genes. We used microarray analysis of human HCT116 colorectal carcinoma cell line to determine the gene expression profile after largazole treatment in comparison with other HDAC inhibitors (FK228 and SAHA). The goal was to identify regulated genes that can be linked to the antiproliferative effects of these HDAC inhibitors in HCT116 cells.
2010-08-28 | GSE22061 | GEO
Project description:Histone deacetylases (HDACs) regulate gene expression. Inhibition of class I HDACs has been shown to inhibit cancer cell growth. Largazole, a new potent HDAC inhibitor, shows strong antitumor activity, presumably by modulating transcription of cancer relevant genes. We used microarray analysis of human HCT116 colorectal carcinoma cell line to determine the gene expression profile after largazole treatment in comparison with other HDAC inhibitors (FK228 and SAHA). The goal was to identify regulated genes that can be linked to the antiproliferative effects of these HDAC inhibitors in HCT116 cells. To characterize the genes regulated by Largazole, SAHA and FK228, genome-wide gene expression analysis was carried out. Human HCT116 colorectal carcinoma cells (400,000) were seeded per well (6-well dish) and one day later treated with Largazole, SAHA, FK228 and vehicle control. 10 h later, total RNA was extracted and processed for hybridization to an Affymetrix Human Genome U133 2.0 GeneChip. Global alterations in transcript levels upon Largazole, SAHA and FK228 treatment were determined through comparison with data derived from cells treated with vehicle control. The experiment was carried out in duplicate.
2010-08-28 | E-GEOD-22061 | biostudies-arrayexpress
Project description:Elevated levels of androgen receptor (AR) in prostate cancer confer resistance to current antiandrogens and play a causal role in disease progression due to persistent target gene activation. Through pharmacologic and genetic approaches, we show that half of all direct AR target genes, including TMPRSS2, the primary driver of ETS fusion transcripts in 70 percent of human prostate cancers, require histone deacetylase (HDAC) activity for transcriptional activation by AR. Surprisingly, the HDAC3-NCoR complex, which typically functions to repress gene expression by nuclear receptors, is required for AR target gene activation. Prostate cancer cells treated with HDAC inhibitors have reduced AR protein levels, but we show that the mechanism of blockade of AR activity is through failure to assemble a coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in hormone refractory prostate cancer models and therefore merit clinical investigation in this setting. HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition. Keywords: Androgen receptor, histone deacetylase, prostate cancer, dose response
2009-01-01 | GSE9000 | GEO
Project description:Members of bromodomain and extra-C terminal (BET) domain family and the histone deacetylase (HDAC) enzyme family efficiently regulate the expression of important oncogenes and tumor suppressors. HDACs induce histone hypoacetylation meanwhile BET proteins bind to acetylated lysines on histones to regulate gene transcription. Here we show that the BET inhibitor JQ1 inhibited proliferation and induced apoptosis of both triple negative and estrogen receptor positive breast cancer cells. Consistent with the critical role of histone acetylation in the regulation of gene expression, microarray analysis revealed broad transcriptional changes after JQ1 or HDAC inhibitor treatment. By examining the molecular pathways affected by the epigenetic inhibitors we found that both BET and HDAC inhibitors are suppressing similar genes that were involved in cell cycle regulation. Combining JQ1 with HDAC inhibitors, we found that the combination significantly decreased cell viability. This effect was partly mediated by the more efficient suppression of genes essential for cell-cycle progression. Furthermore, we detected a dramatic increase in the expression of several members of the USP17 family of deubiquitinating enzymes in response to the single agent treatment, which further increased by the combination treatment. Since constitutive expression of USP17 has been reported to block the Ras/MAPK pathway, our data also suggest that the blockade of the Ras/MAPK pathway might also be involved in the synergistic effect of the combination treatment. In conclusion, this study suggests that co-treatment with BET inhibitors and HDAC inhibitors could be an effective treatment regime in future breast cancer therapy.
2015-09-30 | GSE65495 | GEO
Project description:miRNA expression of myeloma cell lines (MM.1S and KMS-11) cultured with HDAC inhibitors (10 nM panobinostat and 1 uM vorinostat) for 48h.
2024-01-31 | GSE253488 | GEO
Project description:Elevated levels of androgen receptor (AR) in prostate cancer confer resistance to current antiandrogens and play a causal role in disease progression due to persistent target gene activation. Through pharmacologic and genetic approaches, we show that half of all direct AR target genes, including TMPRSS2, the primary driver of ETS fusion transcripts in 70 percent of human prostate cancers, require histone deacetylase (HDAC) activity for transcriptional activation by AR. Surprisingly, the HDAC3-NCoR complex, which typically functions to repress gene expression by nuclear receptors, is required for AR target gene activation. Prostate cancer cells treated with HDAC inhibitors have reduced AR protein levels, but we show that the mechanism of blockade of AR activity is through failure to assemble a coactivator/RNA polymerase II complex after AR binds to the enhancers of target genes. Failed complex assembly is associated with a phase shift in the cyclical wave of AR recruitment that typically occurs in response to ligand treatment. HDAC inhibitors retain the ability to block AR activity in hormone refractory prostate cancer models and therefore merit clinical investigation in this setting. HDAC-regulated AR target genes defined here can serve as biomarkers to ensure sufficient levels of HDAC inhibition. Experiment Overall Design: LNCaP prostate cancer cells were grown in charcoal stripped, androgen deplete medium. They were then stimulated with or without 1nM R1881 and with or without two doses of HDAC inhibitors TSA, SAHA, and LBH 589. Cyclohexamide was include to block new protein synthesis. Cells were harvested 16 hours after treatment.
2009-01-09 | E-GEOD-9000 | biostudies-arrayexpress
Project description:In order to ascertain the potential for histone deacetylase (HDAC) inhibitor-based treatment in non-small cell lung cancer (NSCLC), we analyzed the anti-tumour effects of Trichostatin A (TSA) and suberoylanilide hydroxamic acid (vorinostat) in a panel of 16 NSCLC cell lines via MTT assay. TSA and vorinostat both displayed strong anti-tumor activities in a proportion of NSCLC cell lines, and suggesting the need for the use of predictive markers to select patients receiving this treatment. There was a strong correlation between the responsiveness to TSA and vorinostat (P < 0.0001). To identify a molecular model of sensitivity to HDAC inhibitor treatment in NSCLC, we conducted a gene expression profiling study using cDNA arrays on the same set of cell lines and related the cytotoxic activity of TSA to corresponding gene expression pattern using a modified NCI program. In addition, pathway analysis was performed with Pathway Architect software. We used nine genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine (SVM) algorithm model by which sensitive cell lines were distinguished from resistant cell lines. The prediction performance of the SVM model was validated by an additional seven cell lines, resulting in a prediction value of 100% in respect to determining response to TSA. Our results suggested that [1] HDAC inhibitors may be promising anticancer drugs to NSCLC, and [2] the nine gene classifer is useful in predicting drug sensitivity to HDAC inhibitors and may contribute to achieving individualized therapy for NSCLC patients. training sample set: GSM94303 PC9 GSM94304 PC7 GSM94305 PC14 GSM94306 A549 GSM94308 LK2 GSM94313 RERF LC-KJ GSM94314 RERF LC-MS GSM94315 RERF-LC-AI GSM94316 PC-1 GSM94317 PC-3 GSM94319 PC-10 GSM94323 ABC-1 GSM94324 EBC-1 GSM94325 LC2/ad GSM94328 SQ-5 GSM94329 QG-56 test sample set: GSM94307 LU65 GSM94326 LC1/sq GSM94327 LC-1F GSM254967 LCOK GSM254968 LCD GSM254969 H1650 GSM254970 H1975 Keywords: HDAC inhibitor, NSCLC, cDNA array, drug sensitivity test, pathway analysis
2008-01-08 | GSE10089 | GEO