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Targeting Super-Enhancer-Associated Oncogenes in Oesophageal Squamous Cell Carcinoma (Gut, May 2016)

Jiang YY1, Lin DC2, Mayakonda A1, Hazawa M1, Ding LW1, Chien WW1, Xu L1, Chen Y1, Xiao JF1, Senapedis W3, Baloglu E3, Kanojia D1, Shang L4, Xu X4, Yang H1, Tyner JW5, Wang MR4, Koeffler HP6.

1 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
2 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
3 Department of Drug Discovery, Karyopharm Therapeutics Inc., Newton, Massachusetts, USA.
4 State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
5 Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
6 Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California, Los Angeles School of Medicine, Los Angeles, California, USA National University Cancer Institute, National University Health System and National University of Singapore, Singapore, Singapore.

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 (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.
RESULTS:
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.
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.

PMID: 27196599