Dataset Information

Regulation of NF?B Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

ABSTRACT: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with over 600,000 cases per year. The primary causes for HNSCC include smoking and alcohol consumption, with an increasing number of cases attributed to infection with Human Papillomavirus (HPV). The treatment options for HNSCC currently include surgery, radiotherapy, and/or platinum-based chemotherapeutics. Cetuximab (targeting EGFR) and Pembrolizumab (targeting PD-1) have been approved for advanced stage, recurrent, and/or metastatic HNSCC. Despite these advances, whilst HPV+ HNSCC has a 3-year overall survival (OS) rate of around 80%, the 3-year OS for HPV- HNSCC is still around 55%. Aberrant signal activation of transcription factor NF?B plays an important role in the pathogenesis and therapeutic resistance of HNSCC. As an important mediator of inflammatory signalling and the immune response to pathogens, the NF?B pathway is tightly regulated to prevent chronic inflammation, a key driver of tumorigenesis. Here, we discuss how NF?B signalling is regulated by the ubiquitin pathway and how this pathway is deregulated in HNSCC. Finally, we discuss the current strategies available to target the ubiquitin pathway and how this may offer a potential therapeutic benefit in HNSCC.

SUBMITTER: Morgan EL

PROVIDER: S-EPMC7601648 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

Morgan Ethan L EL Chen Zhong Z Van Waes Carter C

Cancers 20201007 10

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with over 600,000 cases per year. The primary causes for HNSCC include smoking and alcohol consumption, with an increasing number of cases attributed to infection with Human Papillomavirus (HPV). The treatment options for HNSCC currently include surgery, radiotherapy, and/or platinum-based chemotherapeutics. Cetuximab (targeting EGFR) and Pembrolizumab (targeting PD-1) have been approved for advanced stage, ...[more]

PMID: 33036368

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Project description: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.

Dataset Information

Regulation of NF?B Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

Publications

Regulation of NFκB Signalling by Ubiquitination: A Potential Therapeutic Target in Head and Neck Squamous Cell Carcinoma?

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