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Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma

Author

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  • Jiaqiang Dong

    (Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA
    Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, UCLA)

  • Jiong Li

    (Virginia Commonwealth University
    School of Dentistry)

  • Yang Li

    (Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA
    Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, UCLA)

  • Zhikun Ma

    (Virginia Commonwealth University
    School of Dentistry)

  • Yongxin Yu

    (Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA
    Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, UCLA)

  • Cun-Yu Wang

    (Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA
    Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, UCLA
    Henry Samueli School of Engineering and Applied Science, UCLA)

Abstract

Cancer stem cells (CSCs) play a critical role in invasive growth and metastasis of human head and neck squamous cell carcinoma (HNSCC). Although significant progress has been made in understanding the self-renewal and pro-tumorigenic potentials of CSCs, a key challenge remains on how to eliminate CSCs and halt metastasis effectively. Here we show that super-enhancers (SEs) play a critical role in the transcription of cancer stemness genes as well as pro-metastatic genes, thereby controlling their tumorigenic potential and metastasis. Mechanistically, we find that bromodomain-containing protein 4 (BRD4) recruits Mediators and NF-κB p65 to form SEs at cancer stemness genes such as TP63, MET and FOSL1, in addition to oncogenic transcripts. In vivo lineage tracing reveals that disrupting SEs by BET inhibitors potently inhibited CSC self-renewal and eliminated CSCs in addition to elimination of proliferating non-stem tumor cells in a mouse model of HNSCC. Moreover, disrupting SEs also inhibits the invasive growth and lymph node metastasis of human CSCs isolated from human HNSCC. Taken together, our results suggest that targeting SEs may serve as an effective therapy for HNSCC by eliminating CSCs.

Suggested Citation

  • Jiaqiang Dong & Jiong Li & Yang Li & Zhikun Ma & Yongxin Yu & Cun-Yu Wang, 2021. "Transcriptional super-enhancers control cancer stemness and metastasis genes in squamous cell carcinoma," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24137-1
    DOI: 10.1038/s41467-021-24137-1
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    Cited by:

    1. Jing Gao & Xingyu Jiang & Shumin Lei & Wenhao Cheng & Yi Lai & Min Li & Lei Yang & Peifeng Liu & Xiao-hua Chen & Min Huang & Haijun Yu & Huixiong Xu & Zhiai Xu, 2024. "A region-confined PROTAC nanoplatform for spatiotemporally tunable protein degradation and enhanced cancer therapy," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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