Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA184052 | ENA |
REPOSITORIES: ENA
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Project description:The identification of recurrent somatic mutations in genes encoding epigenetic enzymes, coupled with biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases (HMTs) to promoter regions through association with oncogenic fusion proteins such as PML-RARM-NM-1 and AML1-ETO has provided a strong rationale for the development compounds that target the epigenome for the treatment of cancer. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis but it remains unclear why tumor cells are selectively sensitive to HDACi-induced cell death. Herein we assessed the biological and molecular responses of normal and transformed cells to the FDA-approved HDACi vorinostat. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance indicating that specific and selective engagement of the intrinsic apoptosis pathways underlies the tumor cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and identifies molecules and pathways that could underpin the tumor-selective cytotoxic activity of these compounds. Whole genome expression profiling was performed for vorinostat-treated samples and control samples (DMSO vehicle control). Fourteen samples were included in this study. Each sample has three biological replicates, making forty-two arrays in total.
2013-04-22 | E-GEOD-43010 | biostudies-arrayexpress
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:The identification of recurrent somatic mutations in genes encoding epigenetic enzymes, coupled with biochemical studies demonstrating aberrant recruitment of epigenetic enzymes such as histone deacetylases (HDACs) and histone methyltransferases (HMTs) to promoter regions through association with oncogenic fusion proteins such as PML-RARα and AML1-ETO has provided a strong rationale for the development compounds that target the epigenome for the treatment of cancer. HDAC inhibitors (HDACi) are potent inducers of tumor cell apoptosis but it remains unclear why tumor cells are selectively sensitive to HDACi-induced cell death. Herein we assessed the biological and molecular responses of normal and transformed cells to the FDA-approved HDACi vorinostat. Both HDACi selectively killed cells of diverse tissue origin that had been transformed through the serial introduction of different oncogenes. Time course microarray expression profiling revealed that normal and transformed cells transcriptionally responded to vorinostat treatment. Over 4200 genes responded differently to vorinostat in normal and transformed cells and gene ontology and pathway analyses identified a tumor-cell-selective pro-apoptotic gene-expression signature that consisted of BCL2 family genes. In particular, HDACi induced tumor cell-selective upregulation of the pro-apoptotic gene BMF and downregulation of the pro-survival gene BCL2A1 encoding BFL-1. Maintenance of BFL-1 levels in transformed cells through forced expression conferred vorinostat resistance indicating that specific and selective engagement of the intrinsic apoptosis pathways underlies the tumor cell-selective apoptotic activities of these agents. The ability of HDACi to affect the growth and survival of tumor cells whilst leaving normal cells relatively unharmed is fundamental to their successful clinical application. This study provides new insight into the transcriptional effects of HDACi in human donor-matched normal and transformed cells, and identifies molecules and pathways that could underpin the tumor-selective cytotoxic activity of these compounds.
2013-04-22 | GSE43010 | GEO
Project description:Pan and selective HDAC inhibition is synthetically lethal with TRAP1 inhibition in various model systems of glioblastoma, including patient derived xenograft (PDX) cells. Mechanistically, this occurs through several mechanisms, including the induction of metabolic stress by interference with tumor cell energy metabolism accompanied by modulation of pro- and anti-apoptotic Bcl-2 family proteins and the induction of a cell death with apoptotic features.
2020-05-13 | GSE150395 | GEO
Project description:Caspases are cysteine proteases that play a critical role in inflammation and apoptosis. Caspases have a functional role in either the intrinsic apoptotic pathway as initiators of apoptosis or in the extrinsic apoptotic pathway as executioners of apoptosis. Caspase-10 has been speculated to play a principal role as an initiator of apoptosis but the absence of adequate tools, i.e. selective probes, have hindered our understanding of this enzyme as well as the other caspases. Here, we engineered a tobacco etch virus (TEV)-cleavable construct that is compatible with high-throughput screening to identify selective caspase-10 inhibitors. We identified a set of promiscuous caspase inhibitors, including pifithrin-µ (PFT), an inhibitor of p53 transcriptional activity, as well as promising selective pro-caspase-10 and TEV protease inhibitors.
2025-02-04 | PXD053315 | Pride
Project description:Caspases are cysteine proteases that play a critical role in inflammation and apoptosis. Caspases have a functional role in either the intrinsic apoptotic pathway as initiators of apoptosis or in the extrinsic apoptotic pathway as executioners of apoptosis. Caspase-10 has been speculated to play a principal role as an initiator of apoptosis but the absence of adequate tools, i.e. selective probes, have hindered our understanding of this enzyme as well as the other caspases. Here, we engineered a tobacco etch virus (TEV)-cleavable construct that is compatible with high-throughput screening to identify selective caspase-10 inhibitors. We identified a set of promiscuous caspase inhibitors, including pifithrin-µ (PFT), an inhibitor of p53 transcriptional activity, as well as promising selective pro-caspase-10 and TEV protease inhibitors.
2025-02-04 | PXD051710 | Pride
Project description:Regulated by histone acetyltransferases and deacetylases (HDACs), histone acetylation is a key epigenetic mechanism controlling chromatin structure, DNA accessibility, and gene expression. HDAC inhibitors induce growth arrest, differentiation, and apoptosis of tumor cells and are used as anticancer agents. Here we describe the effects of HDAC inhibitors on microbial sensing by macrophages and dendritic cells in vitro and host defenses against infection in vivo. HDAC inhibitors down-regulated the expression of numerous host defense genes, including pattern recognition receptors, kinases, transcription regulators, cytokines, chemokines, growth factors, and costimulatory molecules as assessed by genome-wide microarray analyses or innate immune responses of macrophages and dendritic cells stimulated with Toll-like receptor agonists. HDAC inhibitors induced the expression of Mi-2β and enhanced the DNA-binding activity of the Mi-2/NuRD complex that acts as a transcriptional repressor of macrophage cytokine production. In vivo, HDAC inhibitors increased the susceptibility to bacterial and fungal infections but conferred protection against toxic and septic shock. Thus, these data identify an essential role for HDAC inhibitors in the regulation of the expression of innate immune genes and host defenses against microbial pathogens.
2011-01-01 | GSE22409 | GEO
Project description:Breast cancer has constantly been the leading causes of death in women, and hormone receptor (HR) positive, HER2 negative is the majority subtype. Treatment modalities for HR (+) metastatic breast cancer (mBC) includes endocrine therapy (tamoxifen, fulvestrant, aromatase inhibitors) in addition to targeted therapies (CDK4/6 inhibitors, PI3K/AKT/mTOR inhibitors, histone deacetylase (HDAC) inhibitors, and others. The hippo pathway LATS1/2-YAP/TAZ-TEAD signaling cascade is a fundamentally important pathway that governs multiple essential biological functions in cell biology and cancer biology. YAP/TAZ are often viewed as pro-tumorogenic, however, recent studies support a role of YAP as a tumor suppressor in HR (+) breast cancer due to its inhibition of estrogen signaling. Few studies have investigated the link between HDAC inhibitors and the Hippo pathway. In our study, we demonstrate that HDAC inhibitors induce transcriptional downregulation of YAP expression, while conversely activating a TEAD mediated transcriptional program with upregulation of many Hippo pathway canonical genes. We further identified 4 genes (CCDC80, GADD45A, F3, TGFB2) that were upregulated by HDAC inhibitors and associated with significantly improved survival in a HR (+) breast cancer cohort. We also correlate in patients samples from a clinical cohort of HR (+) metastatic breast cancer that upregulation of Hippo downstream genes are correlated with improved outcomes. Our study provide a novel mechanistic explanation for the clinical benefit of HDAC inhibitors, while providing further experimental support that Hippo-TEAD transcriptional activation profile is associated with better outcomes in HR (+) breast cancer.
2025-03-05 | GSE263971 | GEO
Project description:Chronic Myeloid Leukemia (CML) remains a therapeutic challenge, particularly in patients who develop resistance to standard tyrosine kinase inhibitors (TKIs) such as imatinib. Here, we present the first demonstration of the potent anti-leukemic activity of the histone deacetylase (HDAC) inhibitor martinostat in both TKI-sensitive and TKI-resistant CML. Structural and biochemical analyses confirmed the efficient and selective binding of martinostat to HDAC isoenzyme ligand-binding pockets, resulting in histone and tubulin hyperacetylation in both imatinib-sensitive and resistant CML cells, outperforming vorinostat, a clinically used HDAC inhibitor (HDACi). It selectively impaired CML cell proliferation and viability and induced apoptosis across various CML models, including resistant cell models and patient blasts, with minimal toxicity to healthy cells and low developmental toxicity in zebrafish. In addition to its single-agent efficacy, martinostat demonstrated enhanced anticancer effects when combined with imatinib, both in vitro and in vivo, significantly reducing tumor growth in resistant CML xenograft models. Mechanistically, mRNA-seq data showed that martinostat disrupted key survival signaling pathways and amplified apoptotic responses, thereby contributing to its anticancer activity. These findings highlight the potential of martinostat as a selective, low-toxicity HDACi that, when combined with TKIs, could provide an effective strategy to overcome drug resistance in CML and improve therapeutic outcomes.
2025-07-23 | GSE292088 | GEO
Project description:Activation of Signal Transducer and Activator of Transcription 3 (STAT3) is common in prostate cancers. STAT3 may induce cell proliferation and resistance to apoptosis, as well as promote tumor angiogenesis, invasion, and migration by activating gene expression. Many STAT3-dependent transcriptional responses are mediated through protein-protein interactions that involve the amino-terminal domain (N-domain). In this study, we found that inhibition of the STAT3 N-domain using novel inhibitor ST3-Hel2A-2 induces apoptotic death in prostate cancer cells. The cell death was accomponied by robust activation of pro-apoptotic gene. Using chromatin immunoprecipitation and tiling human promoter arrays (ChIP-chip), we have defined genome-wide targets of STAT3 in DU145 prostate cancer cells. We found that upregulated pro-apoptotic genes were bound by STAT3 in prostate cancer cells, and that STAT3 binding was decreased following inhibition of the STAT3 N-domain. DU145 cells were treated with ST3-Hel2A-2 or DMSO as a control for 3 hr. Total RNA has been extracted and prepared for hybridization on Affymetrix HG-U133A 2.0 arrays.
2010-12-07 | E-GEOD-25866 | biostudies-arrayexpress