title: Targeting super-enhancer-associated oncogenes in oesophageal squamous cell carcinoma.
abstract: 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.
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Yan-Yi
authors.initials: YY
authors.lastname: Jiang
authors.affiliation: 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.
authors.forename: De-Chen
authors.initials: DC
authors.lastname: Lin
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Anand
authors.initials: A
authors.lastname: Mayakonda
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Masaharu
authors.initials: M
authors.lastname: Hazawa
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Ling-Wen
authors.initials: LW
authors.lastname: Ding
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Wen-Wen
authors.initials: WW
authors.lastname: Chien
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Ye
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Jin-Fen
authors.initials: JF
authors.lastname: Xiao
authors.affiliation: Department of Drug Discovery, Karyopharm Therapeutics Inc., Newton, Massachusetts, USA.
authors.forename: William
authors.initials: W
authors.lastname: Senapedis
authors.affiliation: Department of Drug Discovery, Karyopharm Therapeutics Inc., Newton, Massachusetts, USA.
authors.forename: Erkan
authors.initials: E
authors.lastname: Baloglu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Deepika
authors.initials: D
authors.lastname: Kanojia
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Li
authors.initials: L
authors.lastname: Shang
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Xu
authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.affiliation: Department of Cell, Developmental & Cancer Biology, Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Jeffrey W
authors.initials: JW
authors.lastname: Tyner
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute (Hospital), Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Ming-Rong
authors.initials: MR
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: H Phillip
authors.initials: HP
authors.lastname: Koeffler
mesh_terms: D000178:Acrylamides / Q000494:pharmacology*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004354:Drug Screening Assays, Antitumor; D004938:Esophageal Neoplasms / Q000188:drug therapy / Q000235:genetics*; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D050956:HSP40 Heat-Shock Proteins / Q000235:genetics; D057166:High-Throughput Screening Assays; D006801:Humans; D051379:Mice; D009368:Neoplasm Transplantation; D009857:Oncogenes / Q000235:genetics; D010655:Phenylenediamines / Q000494:pharmacology*; D010750:Phosphoproteins / Q000235:genetics; D011743:Pyrimidines / Q000494:pharmacology*; D017423:Sequence Analysis, RNA; D051782:Sterol Regulatory Element Binding Protein 2 / Q000235:genetics; D014157:Transcription Factors; D059467:Transcriptome; D000091102:YAP-Signaling Proteins; D054462:p21-Activated Kinases / Q000235:genetics; D000095043:Cyclin-Dependent Kinase-Activating Kinase
chemical_list: D000178:Acrylamides; D048868:Adaptor Proteins, Signal Transducing; D000631:Aminopyridines; D000970:Antineoplastic Agents; D050676:Core Binding Factor Alpha 2 Subunit; C494647:DNAJB1 protein, human; D050956:HSP40 Heat-Shock Proteins; C000622300:KPT-9274; D010655:Phenylenediamines; D010750:Phosphoproteins; D011743:Pyrimidines; C493728:RUNX1 protein, human; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C000596184:THZ1 compound; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; C116367:PAK4 protein, human; D054462:p21-Activated Kinases; D018844:Cyclin-Dependent Kinases; D000095043:Cyclin-Dependent Kinase-Activating Kinase
keywords: CANCER; CELL BIOLOGY; OESOPHAGEAL CANCER; ONCOGENES