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

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.

• 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
• Journal: Nature communications (Nat Commun) Vol. 9 Issue 1 Pg. 3619 (09 06 2018) ISSN: 2041-1723 [Electronic] England
• PMID: 30190462 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCAT1 long noncoding RNA, human
• RNA, Long Noncoding
• SOX2 protein, human
• SOXB1 Transcription Factors
• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Proteins
• Phosphatidylinositol 3-Kinases
• EGFR protein, human
• ErbB Receptors
• Proto-Oncogene Proteins c-akt
• MAP Kinase Kinase Kinases

Topics

• Animals
• Carcinoma, Squamous Cell (genetics, pathology)
• Cell Line, Tumor
• Enhancer Elements, Genetic
• ErbB Receptors (genetics, metabolism)
• Gene Expression Regulation, Neoplastic
• Humans
• MAP Kinase Kinase Kinases (genetics, metabolism)
• Mice, Inbred NOD
• Phosphatidylinositol 3-Kinases (genetics, metabolism)
• Promoter Regions, Genetic
• Proto-Oncogene Proteins c-akt (genetics, metabolism)
• RNA, Long Noncoding (genetics)
• SOXB1 Transcription Factors (genetics, metabolism)
• Transcription Factors (genetics, metabolism)
• Tumor Suppressor Proteins (genetics, metabolism)
• Xenograft Model Antitumor Assays