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

• DOI: 10.1038/s41467-018-06081-9
• Publication Date: 2018-08-31T14:06:37Z
• Authors: 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; De-Chen Lin; H. Phillip Koeffler
• Keywords: Chromatin immunoprecipitation; Transcription

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 different types SCCs reveal cooperatively lineage-specifically regulate long non-coding RNA (lncRNA) CCAT1 expression, through activation its promoter. Silencing substantially reduces cellular growth both vitro vivo, phenotyping the effect inhibiting either or SOX2. ChIRP analysis shows forms a complex with SOX2, which regulates EGFR expression by binding to EGFR, thereby activating MEK/ERK1/2 PI3K/AKT signaling pathways. These results together identify SCC-specific DNA/RNA/protein activates TP63/SOX2-CCAT1-EGFR cascade promotes SCC tumorigenesis, advancing our understanding dysregulation cancer biology mediated TFs super-enhancers.