Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression

Yuan Jiang, Yan-Yi Jiang (), Jian-Jun Xie, Anand Mayakonda, Masaharu Hazawa, Li Chen, Jin-Fen Xiao, Chun-Quan Li, Mo-Li Huang, Ling-Wen Ding, Qiao-Yang Sun, Liang Xu, Deepika Kanojia, Maya Jeitany, Jian-Wen Deng, Lian-Di Liao, Harmik J. Soukiasian, Benjamin P. Berman, Jia-Jie Hao, Li-Yan Xu, En-Min Li, Ming-Rong Wang, Xin-Gang Bi, Lin De-Chen () and H. Phillip Koeffler
Additional contact information
Yuan Jiang: National University of Singapore
Yan-Yi Jiang: National University of Singapore
Jian-Jun Xie: Medical College of Shantou University
Anand Mayakonda: National University of Singapore
Masaharu Hazawa: Kanazawa University
Li Chen: Cedars-Sinai Medical Center
Jin-Fen Xiao: National University of Singapore
Chun-Quan Li: Harbin Medical University
Mo-Li Huang: National University of Singapore
Ling-Wen Ding: National University of Singapore
Qiao-Yang Sun: National University of Singapore
Liang Xu: National University of Singapore
Deepika Kanojia: National University of Singapore
Maya Jeitany: National University of Singapore
Jian-Wen Deng: Medical College of Shantou University
Lian-Di Liao: Medical College of Shantou University
Harmik J. Soukiasian: Cedars-Sinai Medical Center
Benjamin P. Berman: Cedars-Sinai Medical Center
Jia-Jie Hao: Chinese Academy of Medical Sciences and Peking Union Medical College
Li-Yan Xu: Medical College of Shantou University
En-Min Li: Medical College of Shantou University
Ming-Rong Wang: Chinese Academy of Medical Sciences and Peking Union Medical College
Xin-Gang Bi: Chinese Academy of Medical Sciences and Peking Union Medical College
Lin De-Chen: Cedars-Sinai Medical Center
H. Phillip Koeffler: National University of Singapore

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-06081-9

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