Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma

Yan Yi Jiang, De Chen Lin, Anand Mayakonda, Masaharu Hazawa, Ling Wen Ding, Wen Wen Chien, Liang Xu, Ye Chen, Jin Fen Xiao, William Senapedis, Erkan Baloglu, Deepika Kanojia, Li Shang, Xin Xu, Henry Yang, Jeffrey Tyner, Ming Rong Wang, H. Phillip Koeffler

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

Objectives 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. Design High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIPSeq) 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. Results The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti- OSCC compound, THZ1, a specific CDK7 inhibitor. RNASeq 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. Conclusions 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.

Original languageEnglish (US)
JournalGut
DOIs
StateAccepted/In press - May 10 2016

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Oncogenes
RNA Sequence Analysis
Esophageal Squamous Cell Carcinoma
Investigational Therapies
Chromatin Immunoprecipitation
Cell Lineage
Esophageal Neoplasms
Transcriptome
Cell Biology
Neoplasms
Phosphotransferases
Phenotype
Therapeutics
Genes

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Jiang, Y. Y., Lin, D. C., Mayakonda, A., Hazawa, M., Ding, L. W., Chien, W. W., ... Koeffler, H. P. (Accepted/In press). Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma. Gut. https://doi.org/10.1136/gutjnl-2016-311818

Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma. / Jiang, Yan Yi; Lin, De Chen; Mayakonda, Anand; Hazawa, Masaharu; Ding, Ling Wen; Chien, Wen Wen; Xu, Liang; Chen, Ye; Xiao, Jin Fen; Senapedis, William; Baloglu, Erkan; Kanojia, Deepika; Shang, Li; Xu, Xin; Yang, Henry; Tyner, Jeffrey; Wang, Ming Rong; Koeffler, H. Phillip.

In: Gut, 10.05.2016.

Research output: Contribution to journalArticle

Jiang, YY, Lin, DC, Mayakonda, A, Hazawa, M, Ding, LW, Chien, WW, Xu, L, Chen, Y, Xiao, JF, Senapedis, W, Baloglu, E, Kanojia, D, Shang, L, Xu, X, Yang, H, Tyner, J, Wang, MR & Koeffler, HP 2016, 'Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma', Gut. https://doi.org/10.1136/gutjnl-2016-311818
Jiang, Yan Yi ; Lin, De Chen ; Mayakonda, Anand ; Hazawa, Masaharu ; Ding, Ling Wen ; Chien, Wen Wen ; Xu, Liang ; Chen, Ye ; Xiao, Jin Fen ; Senapedis, William ; Baloglu, Erkan ; Kanojia, Deepika ; Shang, Li ; Xu, Xin ; Yang, Henry ; Tyner, Jeffrey ; Wang, Ming Rong ; Koeffler, H. Phillip. / Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma. In: Gut. 2016.
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abstract = "Objectives 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. Design High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIPSeq) 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. Results The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti- OSCC compound, THZ1, a specific CDK7 inhibitor. RNASeq 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. Conclusions 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.",
author = "Jiang, {Yan Yi} and Lin, {De Chen} and Anand Mayakonda and Masaharu Hazawa and Ding, {Ling Wen} and Chien, {Wen Wen} and Liang Xu and Ye Chen and Xiao, {Jin Fen} and William Senapedis and Erkan Baloglu and Deepika Kanojia and Li Shang and Xin Xu and Henry Yang and Jeffrey Tyner and Wang, {Ming Rong} and Koeffler, {H. Phillip}",
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T1 - Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma

AU - Jiang, Yan Yi

AU - Lin, De Chen

AU - Mayakonda, Anand

AU - Hazawa, Masaharu

AU - Ding, Ling Wen

AU - Chien, Wen Wen

AU - Xu, Liang

AU - Chen, Ye

AU - Xiao, Jin Fen

AU - Senapedis, William

AU - Baloglu, Erkan

AU - Kanojia, Deepika

AU - Shang, Li

AU - Xu, Xin

AU - Yang, Henry

AU - Tyner, Jeffrey

AU - Wang, Ming Rong

AU - Koeffler, H. Phillip

PY - 2016/5/10

Y1 - 2016/5/10

N2 - Objectives 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. Design High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIPSeq) 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. Results The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti- OSCC compound, THZ1, a specific CDK7 inhibitor. RNASeq 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. Conclusions 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.

AB - Objectives 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. Design High-throughput small-molecule inhibitor screening was performed to identify potent anti-OSCC compounds. Whole-transcriptome sequencing (RNA-Seq) and chromatin immunoprecipitation sequencing (ChIPSeq) 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. Results The unbiased high-throughput small-molecule inhibitor screening led us to discover a highly potent anti- OSCC compound, THZ1, a specific CDK7 inhibitor. RNASeq 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. Conclusions 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.

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