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

Jiaqiang Dong, Jiong Li (), Yang Li, Zhikun Ma, Yongxin Yu and Cun-Yu Wang ()
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Jiaqiang Dong: Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA
Jiong Li: Virginia Commonwealth University
Yang Li: Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA
Zhikun Ma: Virginia Commonwealth University
Yongxin Yu: Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA
Cun-Yu Wang: Jonsson Comprehensive Cancer Center and Broad Stem Cell Research Center, UCLA

Nature Communications, 2021, vol. 12, issue 1, 1-14

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24137-1

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