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A Model for Perineural Invasion in Head and Neck Squamous Cell Carcinoma
Published on: January 5, 2017
Therapeutic Targeting of BRD4 in Head Neck Squamous Cell Carcinoma
Yaping Wu1,2, Yanling Wang1, Pengfei Diao1
1Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, Jiangsu 210029, China PRC.
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.
Insights
Bromodomain and extraterminal domain-containing protein 4 (BRD4) is upregulated in head and neck squamous cell carcinoma (HNSCC), driving tumorigenesis. Targeting BRD4 with JQ1 shows therapeutic potential and identifies prognostic biomarkers for HNSCC treatment.
Area of Science:
- Epigenetics and transcriptional regulation
- Oncogenesis and cancer biology
- Head and Neck Squamous Cell Carcinoma (HNSCC) research
Background:
- Bromodomain and extraterminal domain (BET) proteins, including BRD4, function as epigenetic readers and transcriptional coactivators.
- BRD4 is implicated in diverse biological processes and increasingly recognized as a key oncogene and therapeutic target in cancer.
- Understanding BRD4's role in HNSCC is crucial for developing novel treatment strategies.
Purpose of the Study:
- To characterize BRD4 expression and its tumorigenic functions in HNSCC.
- To evaluate the therapeutic potential of targeting BRD4 in HNSCC.
- To identify genes mediating the therapeutic effects of BRD4 inhibition and develop prognostic biomarkers.
Main Methods:
- BRD4 mRNA and protein expression analyzed via bioinformatics, primary HNSCC samples, and a 4NQO-induced HNSCC animal model.
- Tumorigenic roles of BRD4 assessed using genetic and pharmacological approaches in vitro and in vivo.
- Therapeutic efficacy of BRD4 inhibition by JQ1 evaluated across xenograft, 4NQO-induced, and patient-derived xenograft models; gene expression profiling identified JQ1-regulated genes.
Main Results:
- BRD4 was significantly upregulated in HNSCC samples and models, correlating with aggressive features and poorer survival.
- BRD4 depletion inhibited HNSCC cell proliferation, migration, invasion, and reduced tumor growth and metastasis in vivo.
- JQ1 treatment identified numerous antitumor-mediating genes and pathways; a novel prognostic risk score was developed.
Conclusions:
- BRD4 is a critical mediator of HNSCC tumorigenesis and a robust prognostic biomarker.
- Targeting BRD4 with agents like JQ1 presents a promising therapeutic strategy for HNSCC.
- JQ1-regulated genes offer insights into therapeutic mechanisms and patient stratification.
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