Super-enhancer-associated oncogenes as novel therapeutic targets in osteosarcoma (ChIP-seq)
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA555843 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR9723100.fastq.gz | Fastqsanger.gz | |||
| SRR9723101.fastq.gz | Fastqsanger.gz | |||
| SRR9723102.fastq.gz | Fastqsanger.gz | |||
| SRR9723103.fastq.gz | Fastqsanger.gz | |||
| SRR9723094.fastq.gz | Fastqsanger.gz |
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Project description:Despite the development of diagnostic and advanced treatment strategies, the prognosis of patients with osteosarcoma remains poor. A limited understanding of the pathogenesis of osteosarcomas has impeded any improvement in patient outcomes over the past 4 decades. It is thus urgent to identify novel effective targets and treatment regimens for osteosarcoma patients. In this study we delineated the super-enhancer landscape in osteosarcoma cells on the basis of H3K27ac signal intensity by ChIP-Seq and found that super-enhancer-associated genes contribute to the malignant potential of osteosarcoma. THZ2, a novel small molecular inhibitor, shows a powerful anti-osteosarcoma ability through suppress super-enhancer-associated genes selectively. Utilizing the characteristics of super-enhancers in cancer cells, we identified 5 critical super-enhancer-associated oncogenes. With the comparative and retrospective analysis in large numbers of human specimens from patients, these 5 oncogenes were observed closely related with patient prognosis. Our findings determined that targeting super-enhancer-associated oncogenes with transcriptional inhibitor, THZ2, was a promising therapeutic strategy in osteosarcoma, and provided novel candidate targets for patients with osteosarcoma.
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Project description:Super-enhancer-associated oncogenes as novel therapeutic targets in osteosarcoma
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Project description:Super-enhancer-associated oncogenes as novel therapeutic targets in osteosarcoma (Microarray gene expression data)
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Project description:CDK7 is a component of the general transcription factor IIH, which regulates RNAPII initiation and elongation.THZ2, a new molecular inhibitor, can completely inhibit the phosphorylation of the established intracellular CDK7 substrate RNAPII CTD at Ser-2, -5 and -7 through irreversible covalent binding to CDK7. Gene expression profiling was then performed to investigate the THZ2-induced transcription effect, and search the subset of sensitive genes in these 2 osteosarcoma cell lines.
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Project description:Chromatin regulators have become highly attractive targets for cancer therapy, yet many of these regulators are expressed in a broad range of healthy cells and contribute generally to gene expression. An important conundrum has thus emerged: how can inhibition of a general regulator of gene expression produce selective effects at specific oncogenes? Here we investigate how inhibition of the transcriptional coactivator BRD4 (Bromodomain containing 4) leads to selective inhibition of disease-critical oncogenes in a highly malignant blood cancer, multiple myeloma (MM). We found that BRD4 generally occupies the promoter elements of active genes together with the Mediator coactivator, but remarkably high levels of these two coactivator proteins were associated with a small set of exceptionally large enhancers. These super-enhancers are associated with genes that feature prominently in MM biology, including the MYC oncogene. Treatment of MM tumor cells with the BET-bromodomain inhibitor JQ1 led to preferential loss of BRD4 at super-enhancers and consequent transcription elongation defects that preferentially impact genes with super-enhancers, including the c-MYC oncogene. Super-enhancers were found at key oncogenic drivers in many other tumor cells. Thus, super-enhancers can regulate oncogenic drivers in tumor cells, which in some cells can be preferentially disrupted by BRD4 inhibition, which in turn contributes to the selective transcriptional effects observed at these oncogenes. These observations have implications for the discovery of novel cancer therapeutics directed at components of super-enhancers in diverse tumor types. ChIP-Seq for chromatin regulators and RNA Polymerase II in multiple myeloma, glioblastoma multiforme, and small cell lung cancer
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Project description:This SuperSeries is composed of the SubSeries listed below.
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Project description:Medulloblastoma (MB) is the most common malignant pediatric brain tumor and group 3 subtype (G3-MB) exhibits the worst prognosis. Dissecting super-enhancer (SE) driven transcriptional dependencies of cancer has been shown to facilitate identifying novel oncogenic mechanisms and therapeutic targets or strategies. In this study, our integrative SE analyses of primary tissues and patient-derived tumor cell lines of G3-MB revealed their partially conserved SE-associated transcripts were enriched of subtype-specific tumor-dependent genes and MB patients harboring enrichment of those transcripts exhibited worse prognosis. Fourteen such conserved SE-associated genes were identified to be members of SE-driven core transcriptional regulatory network of G3-MB, including three well-recognized master TFs and eleven newly identified effector oncogenes. ARL4D, one of the effector oncogenes, was further demonstrated to exert its oncogenic role via maintaining cell-cycle progression and stemness of G3-MB cells. Moreover, BET inhibition with CDK7 inhibition or proteasome inhibition, two combinatory strategies of targeting SE complex components (BRD4, CDK7) or SE-associated effector oncogene (PSMB5), were shown to exhibit synergistic therapeutic effects against G3-MB. Taken together, our study verifies the oncogenic role and therapeutic potential of SE-driven transcriptional dependencies of G3-MB, resulting in better understanding of its tumor biology and identification of novel SE-associated therapeutic targets or strategies.
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