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Targeting of Super-Enhancer-Associated Oncogenic Transcription in MYCN-driven tumor cells by CDK7 inhibition

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62726 | GEO | 2014/11/21

SECONDARY ACCESSION(S): PRJNA264968

REPOSITORIES: GEO

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CDK7 inhibition suppresses super-enhancer-linked oncogenic transcription in MYCN-driven cancer.

Project description:The MYC oncoproteins are thought to stimulate tumor cell growth and proliferation through amplification of gene transcription, a mechanism that has thwarted most efforts to inhibit MYC function as potential cancer therapy. Using a covalent inhibitor of cyclin-dependent kinase 7 (CDK7) to disrupt the transcription of amplified MYCN in neuroblastoma cells, we demonstrate downregulation of the oncoprotein with consequent massive suppression of MYCN-driven global transcriptional amplification. This response translated to significant tumor regression in a mouse model of high-risk neuroblastoma, without the introduction of systemic toxicity. The striking treatment selectivity of MYCN-overexpressing cells correlated with preferential downregulation of super-enhancer-associated genes, including MYCN and other known oncogenic drivers in neuroblastoma. These results indicate that CDK7 inhibition, by selectively targeting the mechanisms that promote global transcriptional amplification in tumor cells, may be useful therapy for cancers that are driven by MYC family oncoproteins.

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Targeting of Super-Enhancer-Associated Oncogenic Transcription in MYCN-driven tumor cells by CDK7 inhibition [Gene Expression]

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Targeting super-enhancer-driven oncogenic transcription by CDK7 inhibition in anaplastic thyroid cancer

Project description:Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancy and accounts for the majority of thyroid cancer-related deaths. Despite intensive research, there remains no effective treatment for patients with ATC. Here, we identify THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid cancer (PTC) cells, are exceptionally sensitive to CDK7 inhibition. Analyzing both gene expression profiles and super enhancer (SE) features reveals that the SE-mediated oncogenic transcriptional amplification renders the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays discovers a number of novel cancer genes of ATC, including PPP1R15A, SMG9 and KLF2. Inhibition of PPP1R15A with Guanabenz (GBZ) or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, GBZ or THZ1 treatment sensitizes ATC cells to conventional chemotherapy. Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.

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MYCN-targeting miRNAs are predominantly downregulated during MYCN?driven neuroblastoma tumor formation.

Project description:MYCN is a transcription factor that plays key roles in both normal development and cancer. In neuroblastoma, MYCN acts as a major oncogenic driver through pleiotropic effects regulated by multiple protein encoding genes as well as microRNAs (miRNAs). MYCN activity is tightly controlled at the level of transcription and protein stability through various mechanisms. Like most genes, MYCN is further controlled by miRNAs, but the full complement of all miRNAs implicated in this process has not been determined through an unbiased approach. To elucidate the role of miRNAs in regulation of MYCN, we thus explored the MYCN-miRNA interactome to establish miRNAs controlling MYCN expression levels. We combined results from an unbiased and genome-wide high-throughput miRNA target reporter screen with miRNA and mRNA expression data from patients and a murine neuroblastoma progression model. We identified 29 miRNAs targeting MYCN, of which 12 miRNAs are inversely correlated with MYCN expression or activity in neuroblastoma tumor tissue. The majority of MYCN-targeting miRNAs in neuroblastoma showed a decrease in expression during murine MYCN-driven neuroblastoma tumor development. Therefore, we provide evidence that MYCN-targeting miRNAs are preferentially downregulated in MYCN-driven neuroblastoma, suggesting that MYCN negatively controls the expression of these miRNAs, to safeguard its expression.

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