BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA862972 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR20680321_1.fastq.gz | Fastqsanger.gz | |||
| SRR20680321_2.fastq.gz | Fastqsanger.gz | |||
| SRR20680322_1.fastq.gz | Fastqsanger.gz | |||
| SRR20680322_2.fastq.gz | Fastqsanger.gz | |||
| SRR20680323_1.fastq.gz | Fastqsanger.gz |
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Project description:To explore the mechanisms of EGFR/HER2 activation by BET inhibition, we analyzed the mRNA changes in response to BET inhibition.
2022-07-30 | GSE209934 | GEO
Project description:Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation of and vulnerability to the inhibition of MCL1. Drug response and genomics analyses reveal that MCL1 copy-number alterations are associated with effective BET and MCL1 co-targeting. The high frequency of MCL1 chromosomal amplifications (>30%) in basal-like breast cancers suggests that BET and MCL1 co-targeting may have therapeutic utility in this aggressive subtype of breast cancer.
| S-EPMC9523722 | biostudies-literature
Project description:Bromodomain and extra-terminal domain (BET) family inhibitors offer a new approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML) that are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3â to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter and CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2 that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was up-regulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET inhibitor-induced cell death. Kasumi-1 cells were treated with DMSO, 250 nM JQ1, and 125 nM MS417 for 1 and 3 hours, and PRO-seq was performed to study transcriptional changes. Kasumi-1 cells were treated with 250 nM JQ1 for 0, 15, and 30 minutes, and PRO-seq was performed. Two biological replicates were included for each time point. Primary AML patient cells were treated with DMSO and 250 nM JQ1 for 1 hour, and PRO-seq was performed to confirm trancriptional effects of BET inhibitors.
2016-07-15 | E-GEOD-83660 | biostudies-arrayexpress
Project description:Bromodomain and extra-terminal domain (BET) family inhibitors offer a new approach to treating hematological malignancies. We used precision nuclear run-on transcription sequencing (PRO-seq) to create high-resolution maps of active RNA polymerases across the genome in t(8;21) acute myeloid leukemia (AML) that are exceptionally sensitive to BET inhibitors. PRO-seq identified over 1400 genes showing impaired release of promoter-proximal paused RNA polymerases, including the stem cell factor receptor tyrosine kinase KIT that is mutated in t(8;21) AML. PRO-seq also identified an enhancer 3’ to KIT. Chromosome conformation capture confirmed contacts between this enhancer and the KIT promoter and CRISPRi-mediated repression of this enhancer impaired cell growth. PRO-seq also identified microRNAs, including MIR29C and MIR29B2 that target the anti-apoptotic factor MCL1 and were repressed by BET inhibitors. MCL1 protein was up-regulated, and inhibition of BET proteins sensitized t(8:21)-containing cells to MCL1 inhibition, suggesting a potential mechanism of resistance to BET inhibitor-induced cell death.
2016-07-15 | GSE83660 | GEO
Project description:The anti-apoptotic MCL1 protein is a member of the pro-survival BCL2 family and is frequently amplified or elevated in human cancers. MCL1 protein is highly unstable, with its stability being regulated by phosphorylation and ubiquitination. We attempted to identify acetylation as another critical post-translational modification regulating MCL1 protein stability. To this end, 293T cells were transfected with HA-humanMCL1 and Myc-p300. The whole-cell lysates were immunoprecipitated with anti-HA agarose beads. The immunoprecipitated material was resolved by SDS-PAGE, and the MCL1 band was excised for tryptic digestion followed by the MS analysis.
2021-10-14 | MSV000088231 | MassIVE
Project description:MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)) [PMID 23257783]. Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples [GSE11318] and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs. This GEO dataset is comprised of aCGH measurements for DLBCL cell lines, which are used in the above-mentioned paper. Cell lines were measured against the DNA of a healthy male donor who in turn was measured against a pool of healthy DNAs to correct for individual CNVs of the donor.
2013-01-04 | E-GEOD-43272 | biostudies-arrayexpress
Project description:MCL1 is an anti-apoptotic member of the BCL2 family that is deregulated in various solid and hematological malignancies. However, its role in the molecular pathogenesis of diffuse large B-cell lymphoma (DLBCL) is unclear. We analyzed gene expression profiling data from 350 DLBCL patient samples and detected that activated B-cell-like (ABC) DLBCLs express MCL1 at significantly higher levels compared to germinal center B-cell-like (GCB) DLBCL patient samples (p=2.7 x 10(-10)) [PMID 23257783]. Immunohistochemistry confirmed high MCL1 protein expression predominantly in ABC DLBCL in an independent patient cohort (n=249; p=0.001). To elucidate molecular mechanisms leading to aberrant MCL1 expression, we analyzed array comparative genomic hybridization (aCGH) data of 203 DLBCL samples [GSE11318] and identified recurrent chromosomal gains/amplifications of the MCL1 locus that occurred in 26% of ABC DLBCLs. In addition, aberrant STAT3 signaling contributed to high MCL1 expression in this subtype. Knockdown of MCL1 as well as treatment with the BH3-mimetic obatoclax induced apoptotic cell death in MCL1 positive DLBCL cell lines. In summary, MCL1 is deregulated in a significant fraction of ABC DLBCLs and contributes to therapy resistance. These data suggest that specific inhibition of MCL1 might be utilized therapeutically in a subset of DLBCLs.
2013-01-04 | GSE43272 | GEO
Project description:To get insight into the mechanisms of MCL1-induced survival and transformation, we screened 41,000 human genes in a genome-wide gene expression profile analysis of MCL1 over-expressing B-NHL cells. Experiment Overall Design: Two-color (Cy5-CTP/ Cy3-CTP) microarray-based gene expression formats presenting high-density oligonucleotide probes printed on a single glass slide were used (Agilent technologies, Cat No# G4112A whole human genome 41K). Total RNAs from MCL1 over-expressing RAMOS RA-1 and Z-138 B-cells were labeled with Cy5-CTP, whereas RNAs from references (empty vector/ RAMOS RA-1 and empty vector/ Z-138 B-cells) were labeled with Cy3-CTP. After competitive hybridization [RNA-Cy5 from MCL1 over-expressing RAMOS RA-1 or MCL1 over-expressing Z-138 versus RNA-Cy3 from either empty vector/ RAMOS RA-1 or empty vector/ Z-138 respectively] gene expression data were pre-processed using Feature Extraction software and GEPAS tools (http://gepas.bioinfo.cipf.es/).
2008-06-16 | E-GEOD-8834 | biostudies-arrayexpress
Project description:To get insight into the mechanisms of MCL1-induced survival and transformation, we screened 41,000 human genes in a genome-wide gene expression profile analysis of MCL1 over-expressing B-NHL cells. Keywords: MCL1-induced gene expression
2007-08-23 | GSE8834 | GEO
Project description:Our study delves into the intricate dynamics of the integrated stress response (ISR) axis, focusing on the pivotal role of PIM2 kinase and its interaction with the BCL2 family of proteins, revealing crucial mechanisms governing cell survival and tumor progression. Elevated PIM2 expression is a hallmark of various cancers, often correlating with disease aggressiveness. Using a model of normal and malignant plasma cells, we unveil that inhibiting PIM2 kinase triggers not only the production of phosphorylated BAD but also activates ISR-mediated NOXA expression. This shift towards heightened dependence on MCL1 underscores the synergy achieved through combined PIM/MCL1 inhibition, largely propelled by ISR-mediated NOXA expression. In mouse xenograft models, dual targeting of PIM2 and MCL1 effectively controls tumor growth, a response reversed by ISR-specific inhibition, concomitant with the upregulation of genes associated with tumor cell dissemination. These findings illuminate the molecular intricacies of PIM2 inhibition and its implications for cancer therapy, particularly in tumors marked by elevated PIM2 expression.
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