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Co-Activation of Super-Enhancer-Driven CCAT1 by TP63 and SOX2 Promotes Squamous Cancer Progression (Nat Commun, Sep 2018)

Jiang Y1, Jiang YY2, Xie JJ3, Mayakonda A1, Hazawa M4, Chen L5, Xiao JF1, Li CQ6, Huang ML1, Ding LW1, Sun QY1, Xu L1, Kanojia D1, Jeitany M1, Deng JW3, Liao LD7, Soukiasian HJ8, Berman BP9, Hao JJ10, Xu LY7, Li EM3, Wang MR10, Bi XG11, Lin DC12, Koeffler HP1,5,13.

Author information
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
2Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore.
3Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, 515041, China.
4Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, 920-1192, Ishikawa, Japan.
5Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, 90048, USA.
6School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, 163319, China.
7Institute of Oncologic Pathology, Medical College of Shantou University, Shantou, 515041, China.
8Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, USA.
9Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, USA.
10State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
11Department of Urology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China.
12Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, 90048, USA.
13National University Cancer Institute, National University Hospital, Singapore, 119074, Singapore.

Abstract
Squamous cell carcinomas (SCCs) are aggressive malignancies. Previous report demonstrated that master transcription factors (TFs) TP63 and SOX2 exhibited overlapping genomic occupancy in SCCs. However, functional consequence of their frequent co-localization at super-enhancers remains incompletely understood. Here, epigenomic profilings of different types of SCCs reveal that TP63 and SOX2 cooperatively and lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation of its super-enhancers and promoter. Silencing of CCAT1 substantially reduces cellular growth both in vitro and in vivo, phenotyping the effect of inhibiting either TP63 or SOX2. ChIRP analysis shows that CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR expression by binding to the super-enhancers of EGFR, thereby activating both MEK/ERK1/2 and PI3K/AKT signaling pathways. These results together identify a SCC-specific DNA/RNA/protein complex which activates TP63/SOX2-CCAT1-EGFR cascade and promotes SCC tumorigenesis, advancing our understanding of transcription dysregulation in cancer biology mediated by master TFs and super-enhancers.

PMID: 30190462