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 XuEn Min Li, Ming Rong Wang, Xin Gang Bi, De Chen Lin, H. Phillip Koeffler

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

152 Scopus citations

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.

Original languageAmerican English
Article number3619
JournalNature Communications
Volume9
Issue number1
DOIs
StatePublished - 1 Dec 2018
Externally publishedYes

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Publisher Copyright:
© 2018, The Author(s).

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