Theranostics 2019; 9(6):1777-1793. doi:10.7150/thno.31581 This issue Cite

Research Paper

Therapeutic Targeting of BRD4 in Head Neck Squamous Cell Carcinoma

Yaping Wu1,2*, Yanling Wang1*, Pengfei Diao1, Wei Zhang1,3, Jin Li1,2,3, Han Ge1, Yue Song1, Zhongwu Li2, Dongmiao Wang2, Laikui Liu3, Hongbing Jiang2, Jie Cheng1,2✉

1. Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China PRC
2. Department of Oral and Maxillofacial Surgery, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, China PRC
3. Department of Oral Pathology, Affiliated Stomatological Hospital, Nanjing Medical University, Nanjing, 210029, China PRC
*These two authors contributed equally to this study.

Citation:
Wu Y, Wang Y, Diao P, Zhang W, Li J, Ge H, Song Y, Li Z, Wang D, Liu L, Jiang H, Cheng J. Therapeutic Targeting of BRD4 in Head Neck Squamous Cell Carcinoma. Theranostics 2019; 9(6):1777-1793. doi:10.7150/thno.31581. https://www.thno.org/v09p1777.htm
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Abstract

Graphic abstract

The bromodomain and extraterminal family members are epigenetic readers and transcriptional coactivators which are critically involved in various biological processes including tumorigenesis. BRD4 has been increasingly appreciated as a key oncogene and promising anticancer target. Here, we sought to characterize the expression of BRD4 and its tumorigenic roles as well as therapeutic targeting in HNSCC.

Methods: Expression of BRD4 mRNA and protein was determined by bioinformatics interrogation of publically available databases, primary HNSCC samples and 4NQO-induced HNSCC animal model. The tumorigenic roles of BRD4 in HNSCC were evaluated by genetic and pharmacological approach in vitro and in vivo. Therapeutic efficiency of BRD4 targeting by JQ1 was assessed in three preclinical models including xenograft model, 4NQO-induced model and patients-derived xenograft model. Gene candidates responsible for therapeutic effects of JQ1 were identified by transcriptional profiling in HNSCC cells after JQ1 exposure.

Results: Significant upregulation of BRD4 was found in primary HNSCC samples and 4NQO-induced HNSCC model. Its overexpression associated with aggressive clinicopathological features and inferior overall and disease-free survival. BRD4 depletion by genetic silencing or pharmacological inhibition impaired cell proliferation, migration and invasion and reduced tumor growth and metastasis in vivo. Transcriptional profiling of HNSCC cells following JQ1 exposure identified hundreds of genes which might mediated its antitumor effects and enriched in cancer-relevant pathways. A novel prognostic risk score derived from JQ1-regulated genes was developed to stratify patients into subgroups with favorable or inferior prognosis.

Conclusions: Our findings reveal that BRD4 serves as a novel and critical mediator underlying tumorigenesis and a robust prognostic biomarker in HNSCC. Therapeutic targeting of BRD4 represents a potent and promising strategy against HNSCC.

Keywords: BRD4, bromodomain and extraterminal domain, JQ1, head neck squamous cell carcinoma


Citation styles

APA
Wu, Y., Wang, Y., Diao, P., Zhang, W., Li, J., Ge, H., Song, Y., Li, Z., Wang, D., Liu, L., Jiang, H., Cheng, J. (2019). Therapeutic Targeting of BRD4 in Head Neck Squamous Cell Carcinoma. Theranostics, 9(6), 1777-1793. https://doi.org/10.7150/thno.31581.

ACS
Wu, Y.; Wang, Y.; Diao, P.; Zhang, W.; Li, J.; Ge, H.; Song, Y.; Li, Z.; Wang, D.; Liu, L.; Jiang, H.; Cheng, J. Therapeutic Targeting of BRD4 in Head Neck Squamous Cell Carcinoma. Theranostics 2019, 9 (6), 1777-1793. DOI: 10.7150/thno.31581.

NLM
Wu Y, Wang Y, Diao P, Zhang W, Li J, Ge H, Song Y, Li Z, Wang D, Liu L, Jiang H, Cheng J. Therapeutic Targeting of BRD4 in Head Neck Squamous Cell Carcinoma. Theranostics 2019; 9(6):1777-1793. doi:10.7150/thno.31581. https://www.thno.org/v09p1777.htm

CSE
Wu Y, Wang Y, Diao P, Zhang W, Li J, Ge H, Song Y, Li Z, Wang D, Liu L, Jiang H, Cheng J. 2019. Therapeutic Targeting of BRD4 in Head Neck Squamous Cell Carcinoma. Theranostics. 9(6):1777-1793.

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