Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression
Authors: Li-Yan Xu
Jian-Jun Xie
Harmik J Soukiasian
Lian-Di Liao
Liang Xu
Xin-Gang Bi
Jia-Jie Hao
Masaharu Hazawa
Ling-Wen Ding
De-Chen Lin
Jian-Wen Deng
Chun-Quan Li
Benjamin P Berman
Ming-Rong Wang
Mo-Li Huang
Qiao-Yang Sun
Li Chen
Maya Jeitany
Yuan Jiang
Anand Mayakonda
Deepika Kanojia
Yan-Yi Jiang
H Phillip Koeffler
En-Min Li
Jin-Fen Xiao
Journal: Nature Communications (2018)
Discipline: Multidisciplinary
Keywords: Squamous cell carcinomas; master transcription factors; TP63; SOX2; super-enhancers
Affiliations: Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore., Cancer Science Institute of Singapore, National University of Singapore, Singapore, 117599, Singapore. ., Department of Biochemistry and Molecular Biology, Medical College of Shantou University, Shantou, 515041, China., Cell-Bionomics Research Unit, Innovative Integrated Bio-Research Core, Institute for Frontier Science Initiative, Kanazawa University, Kanazawa, 920-1192, Ishikawa, Japan., Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, 90048, USA., School of Medical Informatics, Daqing Campus, Harbin Medical University, Daqing, 163319, China., Institute of Oncologic Pathology, Medical College of Shantou University, Shantou, 515041, China., Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, USA., Center for Bioinformatics and Functional Genomics, Cedars-Sinai Medical Center, Los Angeles, 90048, CA, USA., State 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., Department 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., Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, 90048, USA. ., National 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. 

Retracted: No

PubPeer comments:
 Figure 5e. Much more similar than expected (slightly different exposures). https: imgur.com zcnbiu4 ,