Kinetics after JQ1 treatment in liver cancer cell
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE75908 | GEO | 2016/07/20
SECONDARY ACCESSION(S): PRJNA305698
REPOSITORIES: GEO
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Project description:Analysis of global gene expression after BRD4 inhibition by JQ1 in liver cancer cell lines SK-Hep1 Total RNA obtained from human liver cancer cell line SK-Hep1 cells after treatment of JQ1
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Project description:Methylthioadenosine phosphorylase (MTAP), a key enzyme in the adenine and methionine salvage pathways, catalyzes the hydrolysis of methylthioadenosine (MTA), a compound suggested to affect pivotal cellular processes in part through the regulation of protein methylation. MTAP is expressed in a wide range of cell types and tissues and its deletion is common to cancer cells and in liver injury. The aim of this study was to investigate the proteome and methyl proteome alterations triggered by MTAP deficiency in liver cells to define novel regulatory mechanisms that may explain the pathogenic processes of liver diseases. iTRAQ analysis resulted in the identification of 216 differential proteins (p<0.05) that suggest deregulation of cellular pathways as those mediated by ERK or NFκB. R-methyl proteome analysis lead to the identification of 74 differentially methylated proteins between SK-Hep1 and SK-Hep1+ cells, including 116 new methylation sites. Restoring normal MTA levels in SK-Hep1+ cells parallels the specific methylation of 56 proteins, including KRT8, TGF and CTF8A, which provides a novel regulatory mechanism of their activity with potential implications in carcinogenesis. Inhibition of RNA binding proteins methylation is especially relevant upon accumulation of MTA. As an example, methylation of quaking protein in R242 and R256 in SK-Hep1+ cells may play a pivotal role in the regulation of its activity as indicated by the up-regulation of its target protein p27 kip1. The phenotype associated with a MTAP deficiency was further verified in the liver of MTAP+/- mice. Our data support that MTAP deficiency leads to MTA accumulation and deregulation of central cellular pathways, increasing proliferation and decreasing the susceptibility to chemotherapeutic drugs, which involves differential protein methylation.
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Project description:Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facilitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity against many cancers, mainly through inhibition of c-MYC and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment. JQ1 significantly inhibited the proliferation and survival of OS cells inducing G1 cell cycle arrest, premature senescence, but little effect on apoptosis. Interestingly, c-MYC protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable. Although effective in vitro, JQ1 alone failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice. To overcome the resistance of OS cells to JQ1 treatment, we combined JQ1 with rapamycin, an mTOR inhibitor. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro and in vivo. We also identified that RUNX2 is a direct target of BRD4 inhibition by JQ1 in OS cells. Chromatin immunoprecipitation (ChIP) showed that enrichment of BRD4 protein around RUNX2 transcription start sites diminished with JQ1 treatment in MNNG/HOS cells. Overexpression of RUNX2 protected JQ1-sensitive OS cells from the effect of JQ1, and siRNA-mediated inhibition of RUNX2 sensitized the same cells to JQ1. In conclusion, our findings suggest that JQ1, in combination with rapamycin, is an effective chemotherapeutic option for OS treatment. We also show that inhibition of RUNX2 expression by JQ1 partly explains antiproliferative activity of JQ1 in OS cells. MNNG/HOS cells treated with 7.5mM JQ1, 12.5nM Rapamycin or both were used for RNA extraction and hybridization on Affymetrix microarrays. We compared these microarray samples with the corresponding control (treated with DMSO).
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Project description:To explore genome-wide alteration of BRD4, MED1, p65 and H3K27Ac during BET inhibition, we performed chromatin immunoprecipitation sequencing (ChIP-seq) of SCC1 cells to examine genome-wide recruitment of the MED1, BRD4, p65 and H3K27ac following JQ1 treatment. BET inhibition by JQ1 led to dramatically loss of the recruitment of MED1, BRD4 and p65 at a cohort of key oncogenes associate with tumorigenesis and metastasis. Suggesting BET inhibition is effective strategy to suppress the tumorigenesis and metastasis of head and neck squamous cell carcinoma.
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Project description:Bromodomain and extra terminal domain (BET) proteins are important epigenetic regulators facilitating the transcription of genes in chromatin areas linked to acetylated histones. JQ1, a BET protein inhibitor, has antiproliferative activity against many cancers, mainly through inhibition of c-MYC and upregulation of p21. In this research, we investigated the use of JQ1 for human osteosarcoma (OS) treatment. JQ1 significantly inhibited the proliferation and survival of OS cells inducing G1 cell cycle arrest, premature senescence, but little effect on apoptosis. Interestingly, c-MYC protein levels in JQ1-treated cells remained unchanged, whereas the upregulation of p21 protein was still observable. Although effective in vitro, JQ1 alone failed to reduce the size of the MNNG/HOS xenografts in immunocompromised mice. To overcome the resistance of OS cells to JQ1 treatment, we combined JQ1 with rapamycin, an mTOR inhibitor. JQ1 and rapamycin synergistically inhibited the growth and survival of OS cells in vitro and in vivo. We also identified that RUNX2 is a direct target of BRD4 inhibition by JQ1 in OS cells. Chromatin immunoprecipitation (ChIP) showed that enrichment of BRD4 protein around RUNX2 transcription start sites diminished with JQ1 treatment in MNNG/HOS cells. Overexpression of RUNX2 protected JQ1-sensitive OS cells from the effect of JQ1, and siRNA-mediated inhibition of RUNX2 sensitized the same cells to JQ1. In conclusion, our findings suggest that JQ1, in combination with rapamycin, is an effective chemotherapeutic option for OS treatment. We also show that inhibition of RUNX2 expression by JQ1 partly explains antiproliferative activity of JQ1 in OS cells.
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Project description:The bromodomain inhibitor JQ1 and the histone deacetylase inhibitor panobinostat induce synergistic anticancer effects We analyzed whether JQ1 and panobinostat synergistically modulate gene expression Neuroblastoma SK-N-BE(2) cells were treated with vehicle control, 1 microM JQ1, 10 nM panobinostat, or combination of JQ1 and panobinostat for 6 hours, and subjected to differential gene expression studies with Affymetrix microarrays.
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Project description:Selective bromodomains inhibitors block the interaction between diverse bromodomains and extraterminal domains (BET) proteins and acetylated proteins. These inhibitors have shown beneficial effects in cancers malignancies and experimental inflammation in mouse models, but data on renal diseases are scarce. We have investigated the effect of the BET proteins inhibitor JQ1 in a mice model of unilateral ureteral obstruction. Treatment with JQ1 diminished renal damage, the presence of inflammatory cell infiltration and the upregulation of proinflammatory genes. The in vitro evaluation of JQ1 on TNF-α inducible genes in renal cells showed that BET inhibition modulated several biological processes, including inflammation or immune response. Moreover, gene-silencing experiments showed that BRD4 regulates several proinflammatory genes (IL-6, CCL-2 and CCL-5) and chromatin immunoprecipitation techniques demonstrated that BRD4 specifically binds to acetylated histone H3 in the promoter region of those genes. The nuclear factor-ï«B (NF-ï«B) pathway regulates renal inflammation. The RelA NF-ï«B subunit is activated by acetylation of lysine 310. In damaged kidneys and in TNF-α-treated renal cells, JQ1 blocked the nuclear translocation of RelA/NF-ï«B and NF-ï«B-mediated gene expression. Additionally, obstructed kidneys showed an activation of the Th17 immune response, which was diminished by JQ1 treatment. Our results demonstrate that the BET inhibition decreases renal inflammation by 3 independent mechanisms: 1) chromatin remodelling in the promoter regions of specific genes, 2) blocking NF-ï«B pathway activation, and 3) modulating the Th17 immune response. These results suggest that BET inhibitors could have important therapeutic applications in inflammatory renal diseases. HK2 cell line was treated with JQ1 or its enantiomer JQ1(-) (500nM) for 1 hour before stimulation or not with TNF-α (5ng/ml) for additional 3h. We analized the genes up- and down-regulated by TNF-α vs unstimulated cells, and further the genes downregulated or unaffected by JQ1 compared to the cells treated with the enantiomer (-) JQ1.
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Project description:We performed RNA sequencing (RNA-seq) of HNSCC cells to examine genome-wide gene expression pattern following JQ1 treatment. BET inhibition by JQ1 significantly inhibits a cohort of key oncogenes associate with tumorigenesis and metastasis. Suggesting BET inhibition is effective strategy to suppress the tumorigenesis and metastasis of head and neck squamous cell carcinoma.
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Project description:To set the relevance of BRD4 as repressor, we performed gene expression profile by RNA-seq in A375 treated with BETi JQ1 to identify potential BRD4 target genes.
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Project description:The bromodomain and extra-terminal domain (BET) proteins are promising drug targets for cancer and immune diseases. However, BET inhibition effects have been studied more in the context of bromodomain-containing protein 4 (BRD4) than BRD2, and the BET protein association to histone H4-hyperacetylated chromatin is not understood at the genome-wide level. Here, we report transcription start site (TSS)-resolution integrative analyses of ChIP-seq and transcriptome profiles in human non-small cell lung cancer (NSCLC) cell line H23. We show that di-acetylation at K5 and K8 of histone H4 (H4K5acK8ac) co-localizes with H3K27ac and BRD2 in the majority of active enhancers and promoters, where BRD2 has a stronger association with H4K5acK8ac than H3K27ac. Although BET inhibition by JQ1 led to complete reduction of BRD2 binding to chromatin, only local changes of H4K5acK8ac levels were observed, suggesting that recruitment of BRD2 does not influence global histone H4 hyperacetylation levels. This finding supports a model in which recruitment of BET proteins via histone H4 hyperacetylation is predominant over hyperacetylation of histone H4 by BET protein-associated acetyltransferases. In addition, we found a remarkable number of BRD2-bound genes, including MYC and its downstream target genes, were transcriptionally upregulated upon JQ1 treatment. Using BRD2-enriched sites and transcriptional activity analysis, we identified candidate transcription factors potentially involved in the JQ1 response in BRD2-dependent and independent manner.
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