BCL6 confers KRAS-mutant NSCLCs resistance to BET inhibitors
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA486332 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7702550.fastq.gz | Fastqsanger.gz | |||
| SRR7702551.fastq.gz | Fastqsanger.gz | |||
| SRR7702552.fastq.gz | Fastqsanger.gz | |||
| SRR7702553.fastq.gz | Fastqsanger.gz | |||
| SRR7702554.fastq.gz | Fastqsanger.gz |
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Project description:BCL6 confers KRAS-mutant NSCLCs resistance to BET inhibitors [ChIP-Seq]
| PRJNA490505 | ENA
Project description:We report that BCL6 interacts with BRD3 and that BRD3 inhibition upregulates BCL6. By obtaining sequence from chromatin immunoprecipitated DNA of A549 cells, we generated genome-wide binding gene spectrums of BCL6 and BRD3. By locating -3000 to +200 bps around TSS, we find that BRD3 binds to the promoters of 2470 genes and that BCL6 binds to the promoters of 694 genes, with 82 genes shared by BRD3 and BCL6. Interestingly, BCL6 itself is one of these 82 shared genes, implying that BCL6 mediated self-repression may require the participation of BRD3. Other shared genes includes SGK2, IDH2, HOXB6, SIRT1, SOCS3 and ZFNs, demonstrating the widely involvement of BRD3 in the regulatory role of BCL6. To examine the dependency of BCL6 on BRD3, we also compared BCL6-binding spectrums with or without a BET inhibitor, OTX015. The ChIP-seq data with BCL6 antibody exhibited a diverse BCL-binding spectrum composed of 731 genes in OTX015 treatment, with only 117 genes overlapped with that of DMSO treatment. These data demonstrates that BET inhibition is sufficient to change BCL6-binding spectrum. This study provides a new insight of BCL6 regulatory roles in KRAS-mutant NSCLCs, where BRD3 is recruited by BCL6 and affect BCL6 binding preference as a cofactor.
2018-09-13 | GSE119863 | GEO
Project description:We report that OTX015 upregulates BCL6 in KRAS-mutant NSCLC cells. Considering that both BCL6 and BET proteins regulate target genes by affecting transcription, we performed an RNA-seq experiment to identify downstream genes which response to OTX015. Retinal mRNA profiles of A549 cells treated with DMSO (0.1% for 6 hr) and OTX015 (1 μM for 6 hr) were generated by deep sequencing, in triplicate, using the SOLiD v4 sequencing platform. The sequence reads that passed quality filters were analyzed at the transcript isoform level with two methods: Burrows-Wheeler Aligner (BWA) followed by ANOVA (ANOVA) and TopHat followed by Cufflinks. qRT-PCR validation was performed using TaqMan and SYBR Green assays.
2019-08-15 | GSE118645 | GEO
Project description:Mutational activation of KRAS represents a common oncogenic event in lung cancers and still lacks effective treatments so far. Here, we identify the proto-oncogene B-cell lymphoma 6 (BCL6) as a lynchpin for KRAS dependence. BCL6 transcription was markedly promoted upon inducible activation of KRAS in either LSL-KrasG12D mice lung tumor tissue or engineered KRAS isogenic cell lines. Constitutive expression of BCL6 was also observed in patients with KRAS-mutant lung adenocarcinoma and associated with poor survival. Employing chemical and genetic screens, we characterized that the MAPK/ELK1 axis downstream of KRAS directly regulated BCL6 expression. Genetic depletion or pharmacological inhibitor targeting BCL6 preferentially impedes the proliferation of KRAS-mutant lung cancer cells by suppressing pre-RC protein expression in cycling cells, ultimately leading to stalled replication and DNA damage in vitro. Accordingly, targeted inhibition of BCL6 significantly reduced tumor burden and mortality in LSL-KrasG12D/+ and patient-derived lung cancer xenograft mouse models in vivo. Taken together, these findings reveal an oncogenic role of BCL6 in promoting KRAS-addicted lung cancers and define that BCL6 inhibition confers a targetable vulnerability for this kind of disease.
2022-10-19 | GSE189545 | GEO
Project description:The bromodomain and extra-terminal domain (BET) proteins are promising therapeutic targets to treat refractory solid tumors; however, inherent resistance remains a major challenge in the clinic. Recently, the emerging role of the oncoprotein B cell lymphoma 6 (BCL6) in tumorigenesis and stress response has been unveiled. Here, we demonstrate that BCL6 was upregulated upon BET inhibition in KRAS-mutant cancers, including non-small-cell lung cancer (NSCLC). We further found that BRD3, not BRD2 or BRD4, directly interacted with BCL6 and maintained the negative autoregulatory circuit of BCL6. Disrupting this negative autoregulation by BET inhibitors (BETi) resulted in a striking increase in BCL6 transcription, which further activated the mTOR signaling pathway through repression of the tumor suppressor death-associated protein kinase 2. Importantly, pharmacological inhibition of either BCL6 or mTOR improved the tumor response and enhanced the sensitivity of KRAS-mutant NSCLC to BETi in both in vitro and in vivo settings. Overall, our findings identify a mechanism of BRD3-mediated BCL6 autoregulation and further develop an effective combinatorial strategy to circumvent BETi resistance in KRAS-driven NSCLC.
| S-EPMC7773368 | biostudies-literature
Project description:Bromodomain and extra-terminal domain (BET) proteins are therapeutic targets in several cancers including the most common malignant adult brain tumor glioblastoma (GBM). Multiple small molecule inhibitors of BET proteins have been utilized in preclinical and clinical studies. Unfortunately, BET inhibitors have not shown efficacy in clinical trials enrolling GBM patients. One possible reason for this may stem from resistance mechanisms that arise after prolonged treatment within a clinical setting. However, the mechanisms and timeframe of resistance to BET inhibitors in GBM is not known. To identify the temporal order of resistance mechanisms in GBM we performed quantitative proteomics using multiplex-inhibitor bead mass spectrometry and demonstrated that resistance to BET inhibitors in GBM treatment occurs rapidly within hours and involves the fibroblast growth factor receptor 1 (FGFR1) protein. Small molecule inhibition of BET proteins and FGFR1 simultaneously induces synergy in reducing GBM tumor growth in vitro and in vivo. Further, FGFR1 knockdown synergizes with BET inhibitor mediated reduction of GBM cell proliferation. Collectively, our studies suggest that co-targeting BET and FGFR1 may dampen resistance mechanisms to yield a clinical response in GBM.
2024-06-16 | PXD043214 | Pride
Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2017-07-24 | GSE78213 | GEO
Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2017-07-24 | GSE88871 | GEO
Project description:Bromodomain and extraterminal domain (BET) protein inhibitors are emerging as promising therapeutics of cancers including prostate cancer. The E3 ubiquitin ligase adaptor protein speckle-type POZ protein (SPOP) is implicated in human prostate cancers due to its frequent mutation. Here we demonstrate that SPOP binds to the BET proteins BRD2, BRD3 and BRD4. Wild-type SPOP, but not prostate cancer-associated mutants, promotes polyubiquitination and proteasome degradation of BET proteins by recognizing a common degron motif. BET protein levels are highly elevated in SPOP-mutated prostate cancers in patients. Expression of cancer-derived SPOP mutants upregulates cholesterol biosynthesis genes and confers resistance to the BET inhibitor in cultured prostate cancer cells and tumors in mice, and this effect can be overcome by the AKT inhibitor. Our findings reveal BET proteins as proteolytic targets of SPOP and identify deregulated cholesterol biosynthesis as a downstream event of SPOP mutation-mediated tumorigenesis and therapy resistance in prostate cancer.
2018-03-08 | GSE98010 | GEO
Project description:The BET (bromodomain and extra-terminal) family of acetyl-lysine reader proteins acts as transcriptional activators. BET inhibitors showed anti-cancer efficacies. We performed microarray analysis to characterize BET inhibitor-induced gene expression alterations.
2022-01-01 | GSE168780 | GEO