Targetting super enhancer associated oncogenes in esophageal squamous cell carcinoma
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE76861 | GEO | 2016/05/01
SECONDARY ACCESSION(S): PRJNA308804
REPOSITORIES: GEO
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Project description:Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy and the major histological subtype of esophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of ESCC, few targetable genomic lesions were identified and no molecular-based therapy is available. To identify druggable candidates in this tumor, we performed high-throughput small-molecule inhibitor screening. The unbiased results led us to discover a highly potent anti-ESCC compound, THZ1, a newly developed covalent CDK7 inhibitor. Further in vitro and in vivo experiments showed that THZ1 has powerful anti-neoplastic properties against ESCC cells with minimal toxic effect on healthy tissues. Importantly, whole-transcriptome sequencing (RNA-Seq) revealed that low-dose THZ1 treatment led to selective inhibition of a number of oncogenic transcripts. Notably, further characterization of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with Super-Enhancer (SE). Moreover, SE analysis alone uncovered many lineage-specific master regulators in ESCC. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel oncogenes in the context of ESCC, such as PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase. Together, our integrative molecular approaches identified a catalog of SE-associated lineage-specific master regulators and oncogenic transcripts in ESCC, which will significantly promote the understanding of ESCC biology. The preclinical results of THZ1 may help establish the therapeutic merit of targeting transcriptional regulation program for the treatment of this deadly malignancy.
2016-05-01 | GSE76860 | GEO
Project description:Esophageal squamous cell carcinoma (ESCC) is an aggressive malignancy and the major histological subtype of esophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of ESCC, few targetable genomic lesions were identified and no molecular-based therapy is available. To identify druggable candidates in this tumor, we performed high-throughput small-molecule inhibitor screening. The unbiased results led us to discover a highly potent anti-ESCC compound, THZ1, a newly developed covalent CDK7 inhibitor. Further in vitro and in vivo experiments showed that THZ1 has powerful anti-neoplastic properties against ESCC cells with minimal toxic effect on healthy tissues. Importantly, whole-transcriptome sequencing (RNA-Seq) revealed that low-dose THZ1 treatment led to selective inhibition of a number of oncogenic transcripts. Notably, further characterization of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with Super-Enhancer (SE). Moreover, SE analysis alone uncovered many lineage-specific master regulators in ESCC. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel oncogenes in the context of ESCC, such as PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase. Together, our integrative molecular approaches identified a catalog of SE-associated lineage-specific master regulators and oncogenic transcripts in ESCC, which will significantly promote the understanding of ESCC biology. The preclinical results of THZ1 may help establish the therapeutic merit of targeting transcriptional regulation program for the treatment of this deadly malignancy.
2016-05-01 | GSE76859 | GEO
Project description:Targetting super enhancer associated oncogenes in esophageal squamous cell carcinoma
| PRJNA308804 | ENA
Project description:Oesophageal squamous cell carcinoma (OSCC) is an aggressive malignancy and the major histological subtype of oesophageal cancer. Although recent large-scale genomic analysis has improved the description of the genetic abnormalities of OSCC, few targetable genomic lesions have been identified, and no molecular therapy is available. This study aims to identify druggable candidates in this tumour.High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) were conducted to decipher the mechanisms of action of CDK7 inhibition in OSCC. A variety of in vitro and in vivo cellular assays were performed to determine the effects of candidate genes on OSCC malignant phenotypes.The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti-OSCC compound, THZ1, a specific CDK7 inhibitor. RNA-Seq revealed that low-dose THZ1 treatment caused selective inhibition of a number of oncogenic transcripts. Notably, further characterisation of the genomic features of these THZ1-sensitive transcripts demonstrated that they were frequently associated with super-enhancer (SE). Moreover, SE analysis alone uncovered many OSCC lineage-specific master regulators. Finally, integrative analysis of both THZ1-sensitive and SE-associated transcripts identified a number of novel OSCC oncogenes, including PAK4, RUNX1, DNAJB1, SREBF2 and YAP1, with PAK4 being a potential druggable kinase.Our integrative approaches led to a catalogue of SE-associated master regulators and oncogenic transcripts, which may significantly promote both the understanding of OSCC biology and the development of more innovative therapies.
| S-EPMC5912916 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2018-12-01 | GSE106434 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2019-12-27 | GSE134605 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2024-08-07 | GSE181755 | GEO
Project description:Background & Aims: Lineage-specific expression of long non-coding RNAs (lncRNAs) has been observed recently. However, the underlying mechanism of such specific transcription regulation is unclear. The aim of this study is to identify squamous cell carcinoma (SCC) lineage-specific lncRNAs and to investigate the mechanisms for their expression and function. Methods: Expression characteristics and functions of four candidate SCC-specific lncRNAs were explored. qRT-PCR assays were employed to measure the expression of LINC01503 in 113 tumor/normal matched esophageal SCC (ESCC) cases and its association with survival was determined. The mechanisms underlying LINC01503 function and regulation in ESCC cells were examined using molecular biological methods. Results: Using SCC as a model, we identified a novel super-enhancer (SE)-driven lncRNA, LINC01503, which was uniquely expressed in SCCs such as those from esophagus (ESCC) and head and neck (HNSC). LINC01503 was up-regulated in SCCs and its high expression correlated with poor clinical outcomes. SCC master transcriptional factor TP63 directly bound to a SE at LINC01503 locus and activated its transcription. LINC01503 exhibited strong oncogenic functions in ESCC cell models both in vitro and in vivo. ERK2 and EBP-1 were identified as interacting proteins mediating the effects of LINC01503. Specifically, LINC01503 protected ERK2 from dephosphorylation by DUSP-6, leading to the activation of ERK/MAPK pathway. Similarly, LINC01503 interfered the interaction between EBP-1 and PI3K p85, enhancing Akt signaling pathway. Conclusions: These results demonstrated that LINC01503 is a lineage-specific oncogene in ESCC, which may serve as a potential biomarker and therapeutic target for SCC patients.
2018-12-01 | GSE106433 | GEO
Project description:Background & Aims: Lineage-specific expression of long non-coding RNAs (lncRNAs) has been observed recently. However, the underlying mechanism of such specific transcription regulation is unclear. The aim of this study is to identify squamous cell carcinoma (SCC) lineage-specific lncRNAs and to investigate the mechanisms for their expression and function. Methods: Expression characteristics and functions of four candidate SCC-specific lncRNAs were explored. qRT-PCR assays were employed to measure the expression of LINC01503 in 113 tumor/normal matched esophageal SCC (ESCC) cases and its association with survival was determined. The mechanisms underlying LINC01503 function and regulation in ESCC cells were examined using molecular biological methods. Results: Using SCC as a model, we identified a novel super-enhancer (SE)-driven lncRNA, LINC01503, which was uniquely expressed in SCCs such as those from esophagus (ESCC) and head and neck (HNSC). LINC01503 was up-regulated in SCCs and its high expression correlated with poor clinical outcomes. SCC master transcriptional factor TP63 directly bound to a SE at LINC01503 locus and activated its transcription. LINC01503 exhibited strong oncogenic functions in ESCC cell models both in vitro and in vivo. ERK2 and EBP-1 were identified as interacting proteins mediating the effects of LINC01503. Specifically, LINC01503 protected ERK2 from dephosphorylation by DUSP-6, leading to the activation of ERK/MAPK pathway. Similarly, LINC01503 interfered the interaction between EBP-1 and PI3K p85, enhancing Akt signaling pathway. Conclusions: These results demonstrated that LINC01503 is a lineage-specific oncogene in ESCC, which may serve as a potential biomarker and therapeutic target for SCC patients.
2018-12-01 | GSE106432 | GEO
Project description:This SuperSeries is composed of the SubSeries listed below.
2022-03-16 | GSE188955 | GEO