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

Author

Listed:
  • Yuan Jiang

    (National University of Singapore)

  • Yan-Yi Jiang

    (National University of Singapore)

  • Jian-Jun Xie

    (Medical College of Shantou University)

  • Anand Mayakonda

    (National University of Singapore)

  • Masaharu Hazawa

    (Kanazawa University)

  • Li Chen

    (Cedars-Sinai Medical Center)

  • Jin-Fen Xiao

    (National University of Singapore)

  • Chun-Quan Li

    (Harbin Medical University)

  • Mo-Li Huang

    (National University of Singapore)

  • Ling-Wen Ding

    (National University of Singapore)

  • Qiao-Yang Sun

    (National University of Singapore)

  • Liang Xu

    (National University of Singapore)

  • Deepika Kanojia

    (National University of Singapore)

  • Maya Jeitany

    (National University of Singapore)

  • Jian-Wen Deng

    (Medical College of Shantou University)

  • Lian-Di Liao

    (Medical College of Shantou University)

  • Harmik J. Soukiasian

    (Cedars-Sinai Medical Center)

  • Benjamin P. Berman

    (Cedars-Sinai Medical Center)

  • Jia-Jie Hao

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Li-Yan Xu

    (Medical College of Shantou University)

  • En-Min Li

    (Medical College of Shantou University)

  • Ming-Rong Wang

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • Xin-Gang Bi

    (Chinese Academy of Medical Sciences and Peking Union Medical College)

  • De-Chen Lin

    (Cedars-Sinai Medical Center)

  • H. Phillip Koeffler

    (National University of Singapore
    Cedars-Sinai Medical Center
    National University Hospital)

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.

Suggested Citation

  • 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 J, 2018. "Co-activation of super-enhancer-driven CCAT1 by TP63 and SOX2 promotes squamous cancer progression," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-06081-9
    DOI: 10.1038/s41467-018-06081-9
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    Cited by:

    1. Yuan Jiang & Yueyuan Zheng & Yuan-Wei Zhang & Shuai Kong & Jinxiu Dong & Fei Wang & Benjamin Ziman & Sigal Gery & Jia-Jie Hao & Dan Zhou & Jianian Zhou & Allen S. Ho & Uttam K. Sinha & Jian Chen & Shu, 2024. "Reciprocal inhibition between TP63 and STAT1 regulates anti-tumor immune response through interferon-γ signaling in squamous cancer," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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