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

• Published in: Nature communications Vol. 9; no. 1; pp. 3619 - 13
• Main Authors: Jiang, Yuan, Jiang, Yan-Yi, Xie, Jian-Jun, Mayakonda, Anand, Hazawa, Masaharu, Chen, Li, Xiao, Jin-Fen, Li, Chun-Quan, Huang, Mo-Li, Ding, Ling-Wen, Sun, Qiao-Yang, Xu, Liang, Kanojia, Deepika, Jeitany, Maya, Deng, Jian-Wen, Liao, Lian-Di, Soukiasian, Harmik J., Berman, Benjamin P., Hao, Jia-Jie, Xu, Li-Yan, Li, En-Min, Wang, Ming-Rong, Bi, Xin-Gang, Lin, De-Chen, Koeffler, H. Phillip
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 06.09.2018; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 13/109; 13/89; 45/15; 45/77; 45/88; 45/90; 45/91; 631/67; 631/67/1504; 631/67/1536; 631/67/1612; 631/67/395; 82/1; 82/80; Activation; AKT protein; Animals; Biology; Cancer; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; Cell Line, Tumor; Deoxyribonucleic acid; DNA; Enhancer Elements, Genetic; Enhancers; Epidermal growth factor receptors; ErbB Receptors - genetics; ErbB Receptors - metabolism; Gene expression; Gene Expression Regulation, Neoplastic; Genes; Genomics; Humanities and Social Sciences; Humans; Localization; MAP Kinase Kinase Kinases - genetics; MAP Kinase Kinase Kinases - metabolism; Medical schools; Mice, Inbred NOD; multidisciplinary; Non-coding RNA; Phenotyping; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Promoter Regions, Genetic; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; Ribonucleic acid; RNA; RNA polymerase; RNA, Long Noncoding - genetics; Science; Science (multidisciplinary); SOXB1 Transcription Factors - genetics; SOXB1 Transcription Factors - metabolism; Squamous cell carcinoma; Stem cells; Transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis; Xenograft Model Antitumor Assays
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-06081-9

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. Master regulator transcription factors TP63 and SOX2 have been reported to overlap in genomic occupancy in squamous cell carcinomas (SCCs). Here, the authors demonstrate that TP63 and SOX2 promote co-operatively long non-coding RNA CCAT1 expression through activating its super-enhancer, and CCAT1 forms a complex with TP63 and SOX2, which regulates EGFR super-enhancers and enhances both the MEK/ERK1/2 and PI3K/AKT signaling pathways in SCC.