Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA339566 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR4044970_1.fastq.gz | Fastqsanger.gz | |||
| SRR4044970_2.fastq.gz | Fastqsanger.gz | |||
| SRR4044980_1.fastq.gz | Fastqsanger.gz | |||
| SRR4044980_2.fastq.gz | Fastqsanger.gz | |||
| SRR4044990_1.fastq.gz | Fastqsanger.gz |
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Project description:Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related death worldwide because of late stage detection when curative therapy is not available. The bromodomain and extraterminal (BET) protein BRD4 activates gene expression by interacting with histone H3K27-acetylated (H3K27Ac) chromatin. AZD5153 is an orally bioavailable, potent, bivalent BRD4 inhibitor, currently undergoing clinical trials in lymphoma and ovarian cancer patients. Here, we studied therapeutic potential of AZD5153 against HCC and elucidated the underlying mechanism. In conclusion, our results in preclinical models indicate that the combined effect of AZD5153 could be a novel targeted therapy for HCC and provides rationale for clinical trials of an AZD5153-FK866 combination as an effective and attractive strategy to treat this deadly disease.
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Project description:Natural killer cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a combined chemico-genetic approach, we have identified that BET bromodomains BRD2 and BRD4 are central regulators of NK cell responses. We show that both BRD2 and BRD4 play a key regulatory function in controlling NK cell specific inflammatory responses. However, knockdown of BRD2 but not BRD4 impairs NK cell cytolytic response, highlighting a redundant role for BRD4 in regulating NK cell killing. We further show that the prototypic monovalent BET inhibitor impairs in vitro NK cell mediated killing of cancer target cells, while the bivalent BET bromodomain AZD5153 does not. We ascribe these differences to the preferential affinity of JQ1(+) to BRD2, while AZD5153 has a higher affinity for BRD4. Our work suggests that inhibiting BET bromodomains may be an effective therapeutic strategy for controlling inflammatory function. Given that BRD2 but not BRD4 inhibition can impair NK cell mediated killing, our findings also have clinical significance in light of the ongoing clinical application of BET bromodomains in oncology.
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Project description:Cyclin-dependent kinase 9 (CDK9) stimulates oncogenic transcriptional pathways in cancer. Here, we evaluate the activity of an orally bioavailable CDK9 inhibitor, CDKI-73, in prostate cancer, a disease characterized by aberrant activity of multiple transcriptional regulators. CDKI-73 caused inhibition of proliferation and cell death in diverse in vitro models of androgen receptor (AR)-driven and AR-independent models of castration-resistant prostate cancer (CRPC). The activity of CDKI-73 was validated in more clinically-relevant systems, including xenografts, patient-derived tumor explants and aggressive patient-derived CRPC organoids. Mechanistically, CDKI-73 inhibited CDK9-mediated phosphorylation of serine 2 on RNA polymerase II and serine 81 on AR. This resulted in reduced levels of anti-apoptotic factors and suppression of signaling pathways regulated by AR, MYC and BRD4, key drivers of dysregulated transcription in prostate cancer. CDKI-73 synergized with the BRD4 inhibitor AZD5153 in cell lines and organoid models of aggressive AR-driven and AR-independent disease. Collectively, our work provides new insights into CDK9’s oncogenic activity and reveals CDKI-73 as a promising therapeutic agent for prostate cancer, particularly aggressive, therapy-resistant subtypes.
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Project description:Transcriptional changes by PARP7 inhibitor in cancer cell lines
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Project description:The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression. BRD4 is an important chromatin regulator with roles in gene regulation, DNA damage, cell proliferation and cancer progression1-4. The protein is recruited to distinct genomic loci by the interaction of its tandem bromodomains with acetylated lysines on histones and other nuclear proteins5. There, BRD4 acts as a transcriptional activator by P-TEFb-mediated stimulation of transcriptional elongation6. The activating function of BRD4 on key driver oncogenes like MYC have made this epigenetic enzyme an important therapeutic target in both BRD4 translocated and BRD4 wild-type cancers3,7-12, and at least seven bromodomain inhibitors have reached the clinical stage13. Genome-wide studies have identified the role of BRD4-induced epigenetic heterogeneity in cancer cell resistance14, and factors defining BRD4 inhibitor response15,16. However, despite its clinical importance and the broad role of BRD4 in chromatin organization, surprisingly little is known about factors that are directly required for BRD4 function. To systematically expand the list of known BRD4 interactors5 and to characterize proteins directly required for BRD4 function, we developed a strategy of two complementary screens for genetic and physical partners of BRD4. The two approaches converge on a single factor, methylenetetrahydrofolate dehydrogenase 1 (MTHFD1). Our description of a transcriptional role for this C-1-tetrahydrofolate synthase highlights a direct connection between nuclear folate metabolism and cancer regulation.
2019-04-04 | PXD013090 | Pride
Project description:Knockdown of the oncogene, BRD4-NUT, in a rare cancer, termed NUTmidline carcinoma (NMC), results in morphologic features consistent with squamous differentiation. Treatment with the HDAC-inhibitor, TSA, appears to cause the same phenotype. Here, we use gene expression profiling to compare the changes in gene expression following BRD4-NUT knockdown and TSA treatment. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following siRNA knockdown versus control in duplicate. RNA was extracted from two BRD4-NUT-expressing NMC cell lines, PER-403 and TC-797, 24h following treatment with TSA versus etoh control in triplicate
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