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GSE87289
Homo sapiens
3 Downloadable Samples
Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Epigenetic regulation of gene expression by histone modification has emerged as a major facet of physiologic and disease processes. As a result, there has been intense interest in developing epigenetic therapies leading to the discovery of small molecule agents that target proteins involved in histone modification. Several histone deacetylase (HDAC) inhibitors are now approved drugs for a specialized group of hematologic malignancies but not yet for a wider range of cancer types including solid tumors. One of the conceptual challenges in targeting HDACs is that even selective class I HDAC inhibitors likely impact these deacetylase activities indiscriminately across a range of distinct HDAC-containing multiprotein complexes. Such broad cellular effects may result in a narrow therapeutic window between disease efficacy and toxicity. Among HDAC complexes, the CoREST complex, which includes HDAC1 or its close paralog HDAC2, the scaffolding protein CoREST, and lysine specific demethylase 1 (LSD1) has attracted special interest. Here we report corin2, designed to dually inhibit the CoREST complex major enzymatic activities, lysine specific demethylase 1 (LSD1) and HDACs 1/2. Corin2 is a synthetic hybrid agent derived from the class I HDAC inhibitor (entinostat) and an LSD1 inhibitor (tranylcypromine analog). Enzymologic analysis reveals that corin2 selectively targets the CoREST complex and shows more sustained inhibition of the CoREST complex HDAC activity than entinostat. Cell-based experiments demonstrate that corin2 exhibits a superior anti-proliferative profile against several melanoma lines compared to its parent monofunctional HDAC and LSD1 inhibitors (alone or in combination) but is less toxic to non-cancerous primary human melanocytes. Transcriptomics analysis shows that corin2 is a more powerful inducer of tumor suppressor genes relative to the parent HDAC and LSD1 compounds (alone or in combination). Genetic knockdown of CoREST or LSD1 in cancer cell lines abolishes the differences in potency of corin2 vs. entinostat, suggesting that corin2's favorable pharmacologic effects rely on an intact CoREST complex. Corin2 was also effective in slowing tumor growth in a melanoma mouse xenograft model. These studies highlight the promise of a new class of two-pronged hybrid agents that selectively target particular epigenetic regulatory complexes and offer unique therapeutic opportunities.
Publication Title
Targeting the CoREST complex with dual histone deacetylase and demethylase inhibitors.
Sample Metadata Fields
Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 2.0 ST Array (hugene20st)
Description
Microarray gene expression profiling reveals that PHGDH inhibition by NCT-503 activates a metabolic stress response characterized by downregulation of cell cycle genes and induction of stress response genes.
Publication Title
Metabolic Reprogramming by MYCN Confers Dependence on the Serine-Glycine-One-Carbon Biosynthetic Pathway.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Mus musculus
- 42 Downloadable Samples
- Affymetrix Mouse Genome 430 2.0 Array (mouse4302)
Description
The macrophage-Brucella interaction is critical for the establishment of a chronic Brucella infection. Smooth virulent B. suis strain 1330 (S1330) prevents macrophage cell death. However, rough attenuated B. suis strain VTRS1 induces strong macrophage cell death. To further investigate the mechanism of VTRS1-induced macrophage cell death, microarrays were used to analyze temporal transcriptional responses of murine macrophage-like J774. A1 cells infected with S1330 or VTRS1.
Publication Title
Proinflammatory caspase-2-mediated macrophage cell death induced by a rough attenuated Brucella suis strain.
Sample Metadata Fields
Cell line, Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
MEIS2 has an important role in development and organogenesis, and is implicated in the pathogenesis of human cancer. The molecular basis of MEIS2 action in tumorigenesis is not clear. Here, we show that MEIS2 is highly expressed in human neuroblastoma cell lines and is required for neuroblastoma cell survival and proliferation. Depletion of MEIS2 in neuroblastoma cells leads to M phase arrest and mitotic catastrophe, whereas ectopic expression of MEIS2 markedly enhances neuroblastoma cell proliferation, anchorage-independent growth, and tumorigenicity. Gene expression profiling reveals an essential role of MEIS2 in maintaining the expression of a large number of late cell cycle genes, including those required for DNA replication, G2-M checkpoint control and M phase progression. Importantly, we identify MEIS2 as a transcription activator of the MuvB-BMYB-FOXM1 complex that functions as a master regulator of mitotic gene expression. Further, we show that FOXM1 is a direct target gene of MEIS2 and is required for MEIS2 to upregulate mitotic genes. These findings link a development gene to the control of cell cycle progression and suggest that high MEIS2 expression is a molecular mechanism for high expression of mitotic genes that is commonly observed in cancers of poor prognosis.
Publication Title
MEIS2 is essential for neuroblastoma cell survival and proliferation by transcriptional control of M-phase progression.
Sample Metadata Fields
Cell line, Treatment
View Samples- Mus musculus
- 6 Downloadable Samples
- Affymetrix Mouse Gene 1.0 ST Array (mogene10st)
Description
Abnormal NF-kB2 activation has been reported in several types of human leukemia and lymphomas although the exact mechanisms and affected pathways are not clear. We have investigated these questions through the use of a unique transgenic mouse model with lymphocyte-targeted expression of p80HT, a lymphoma associated NF-kB2 mutant. Microarray analysis, verified at the RNA and protein level identified new downstream targets and confirmed established regulatory networks. 201 genes were significantly changed, with 126 being upregulated and 75 downregulated. Pathway analysis uncovered both known and unknown interactions between factors important in the development of human B cell lymphomas and multiple myeloma, including cyclins D1 and D2, TRAF1, CD27, BIRC5/survivin, IL-15 and IL-10. Critical roles for STAT3 and TNF receptors are highlighted. Six target genes of STAT3 were identified: cyclins D1and D2, IL-10, survivin, IL-21 and Blimp1. Interfering with STAT3 signaling induced apoptosis in multiple myeloma cell lines. Novel pathways for NF-kB2 are proposed that involve IL-10 and other genes in the differentiation of plasma cells, evasion of apoptosis and proliferation. These pathways were verified with publically available human microarrays. Several treatment strategies based on these findings are discussed.
Publication Title
NF-κB2 mutation targets survival, proliferation and differentiation pathways in the pathogenesis of plasma cell tumors.
Sample Metadata Fields
Specimen part
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Increased activation of the serine-glycine biosynthetic pathway is an integral part of cancer metabolism that drives macromolecule synthesis needed for cell proliferation. Whether this pathway is under epigenetic control is unknown. Here we show that the histone H3 lysine 9 (H3K9) methyltransferase G9A is required for maintaining the pathway enzyme genes in an active state marked by H3K9 monomethylation and for the transcriptional activation of this pathway in response to serine deprivation. G9A inactivation depletes serine and its downstream metabolites, triggering cell death with autophagy in cancer cell lines of different tissue origins. Higher G9A expression, which is observed in various cancers and is associated with greater mortality in cancer patients, increases serine production and enhances the proliferation and tumorigenicity of cancer cells. These findings identify a G9A-dependent epigenetic program in the control of cancer metabolism, providing a rationale for G9A inhibition as a therapeutic strategy for cancer.
Publication Title
The histone H3 methyltransferase G9A epigenetically activates the serine-glycine synthesis pathway to sustain cancer cell survival and proliferation.
Sample Metadata Fields
Treatment
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
This SuperSeries is composed of the SubSeries listed below.
Publication Title
HOXC9 directly regulates distinct sets of genes to coordinate diverse cellular processes during neuronal differentiation.
Sample Metadata Fields
Specimen part, Cell line
View Samples- Homo sapiens
- 6 Downloadable Samples
- Affymetrix Human Gene 1.0 ST Array (hugene10st)
Description
Cell differentiation is an essential process of normal development by which a stem cell or progenitor cell becomes a post-mitotic, specialized cell with unique morphology and function. Also, it has long been recognized that differentiation is associated with a marked reduction in DNA damage response at the global level. The molecular basis for the coordination between cell cycle exit, acquirement of specialized structure and function, and attenuation of DNA damage response during differentiation is not well understood. We have conducted a genome-wide analysis of the HOXC9-induced neuronal differentiation program in human neuroblastoma cells. Gene expression profiling reveals that HOXC9-induced differentiation is associated with transcriptional regulation of 2,395 genes, which is characterized by global upregulation of neuronal genes and downregulation of cell cycle and DNA repair genes. Remarkably, genome-wide mapping demonstrates that HOXC9 occupies 40% of these genes, including a large number of genes involved in neuronal differentiation, cell cycle progression and DNA damage response. These findings suggest that HOXC9 directly activates and represses the transcription of distinct sets of genes to coordinate the cellular events characteristic of neuronal differentiation.
Publication Title
HOXC9 directly regulates distinct sets of genes to coordinate diverse cellular processes during neuronal differentiation.
Sample Metadata Fields
Cell line
View Samples- Rattus norvegicus
- 43 Downloadable Samples
- Affymetrix Rat Expression 230A Array (rae230a)
Description
Neurodegenerative brain disorders become more common in the aged. Most of these disorders are associated with or caused by selective death of certain neuronal subpopulations. The mechanisms underlying the differential vulnerability of certain neuronal populations are still largely unexplored and few neuroprotective treatments are available to date. Elucidation of these mechanisms may lead to a greater understanding of the pathogenesis and treatment of neurodegenerative diseases. Moreover, preconditioning by a short seizure confers neuroprotection following a subsequent prolonged seizure. Our goal is to identify pathways that confer vulnerability and resistance to neurotoxic conditions by comparing the basal and preconditioned gene expression profiles of three differentially vulnerable hippocampal neuron populations.
Publication Title
Gene expression changes after seizure preconditioning in the three major hippocampal cell layers.
Sample Metadata Fields
No sample metadata fields
View Samples- Mus musculus
- 16 Downloadable Samples
- Illumina mouseRef-8 v1.1 expression beadchip
Description
We performed gene expression microarray analysis of the hypothalamic response to starvation in neonatal wild-type mice, and in Snord116del mice that are a mouse model for PWS. This study is motivated by the neonatal feeding problems observed in several genetic diseases including Prader-Willi syndrome (PWS). Later in life, individuals with PWS develop hyperphagia and obesity due to lack of appetite control. We hypothesize that failure to thrive in infancy and later-onset hyperphagia may be related and could be due to a defect in the hypothalamus. In this study, we performed gene expression microarray analysis of the hypothalamic response to starvation in neonatal wild-type mice, and in Snord116del mice that are a mouse model for PWS. The neonatal starvation response was dramatically different from that reported in adult rodents. Genes that are affected by adult starvation are not changed in the hypothalamus of 5 day-old pups that were starved for 6 hrs. Unlike in adult rodents, expression levels of Nanos2 and Pdk4 were increased, and those of Pgpep1, Ndph, Brms1l, Mett10d, and Snx1 were decreased after fasting. In addition, we compared hypothalamic gene expression profiles at days 5 and 13 to document developmental changes. Notably, the gene expression profiles of Snord116del deletion mice and wild-type littermates were very similar at both postnatal days 5 and 13, and after starvation.
Publication Title
Neonatal maternal deprivation response and developmental changes in gene expression revealed by hypothalamic gene expression profiling in mice.
Sample Metadata Fields
No sample metadata fields
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