Role of p300 in HPV-positive Head and Neck Cancer

p300 在 HPV 阳性头颈癌中的作用

• 批准号: 8818485
• 负责人: Paramjit S Arora
• 金额: $ 49.93万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-06 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8818485
• 关键词: Acetylation; Acetyltransferase; Alleles; Apoptosis; Binding; Biochemical; Biological; Carcinoma; Cell Proliferation; Cell Survival; Cells; Chemicals; Chromatin; Cisplatin; DNA Binding; DNA Damage; Data; Development; E2F1 gene; EP300 gene; Ensure; Epidemic; Epidemiology; Epithelial Cells; Europe; Exposure to; Future; Genetic Transcription; Head and Neck Squamous Cell Carcinoma; Histones; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; In Vitro; Knock-out; Lead; Ligands; Malignant Epithelial Cell; Mediating; Molecular Mechanisms of Action; Molecular Target; Oropharyngeal; Pathogenesis; Patients; Phenotype; Prevalence; Process; Protein p53; Proteins; Radiation; Recruitment Activity; Reporting; Resolution; Resources; Retinoblastoma Protein; Risk Factors; Role; Specificity; Stimulus; Time; Tumorigenicity; United States; Work; Xenograft procedure; anti-cancer therapeutic; base; chemical genetics; design; dosage; functional restoration; high risk; in vivo; innovation; oral HPV-positive head and neck cancers; overexpression; promoter; prototype; public health relevance; response; restoration; scaffold; small molecule; tool; transcription factor; tumorigenesis

DESCRIPTION (provided by applicant): Recent evidence supports the recognition that HPV infection is a major risk factor for head and neck squamous cell carcinoma (HNSCC), in particular oropharyngeal SCC. High-risk HPV16 is by far the most frequent, ~90%, HPV type detected in HNSCC. Epidemiological data indicate that the prevalence of HPV-positive HNSCC has rapidly increased by about 3-fold in the past three decades in the United States and Europe (2-4). Based on these alarming numbers, it has been suggested that an epidemic of HPV-positive HNSCC will emerge in the near future. Additional work to probe the mechanism of action of HPV-induced tumorigenesis is needed to reveal actionable "druggable" targets for the development of HPV-directed anti-cancer therapeutics. p300, a transcriptional co-activator, controls gene transcription through multiple mechanisms; as an acetyltransferase to acetylate histones and transcription factors, as a scaffold for transcription factors on chromatin, and as a bridge to connect transcription factor to the transcriptional machinery. Interestingly, single allee knockout of p300 has distinct transcriptional phenotypes revealing that promoter bound transcription factors are likely to be in competition to recruit limited amounts of p300. HPV16E6 was reported to bind to p300 at the CH1, CH3, and C-terminus domains whereas HPV16E7 binds to the CH1 and CH3 domains. Since p300 is a limited resource, it is likely that HPV16E6 and HPV16E7 co-opt host p300 to control p300 function in HPV16-positive HNSCC cells. Our main hypothesis is that restoration of host p300 function may be an approach to reactivate p53/pRb and reverse HPV16-induced transformation of epithelial cells. In this application, biochemical and chemical approaches will be used to probe the interaction between HPV16E6/E7 and p300 in HPV16-positive HNSCC. The molecular mechanism of action for p300 domain ligands will be defined in vitro and in vivo.

描述（由申请人提供）：最近的证据支持HPV感染是头颈部鳞状细胞癌（HNSCC），特别是口咽部鳞状细胞癌的主要风险因素的认识。高危型HPV 16是迄今为止在HNSCC中检测到的最常见的HPV类型，约90%。流行病学数据表明，HPV阳性HNSCC的患病率在过去三十年中在美国和欧洲迅速增加了约3倍（2-4）。基于这些令人震惊的数字，有人认为HPV阳性HNSCC的流行病将在不久的将来出现。探索HPV诱导的肿瘤发生的作用机制的额外工作需要揭示用于开发HPV导向的抗癌疗法的可操作的“可药物化”靶点。p300是一种转录辅激活因子，通过多种机制控制基因转录;作为乙酰转移酶使组蛋白和转录因子乙酰化，作为转录因子在染色质上的支架，以及作为连接转录因子和转录机器的桥梁。有趣的是，p300的单一等位基因敲除具有不同的转录表型，揭示了启动子结合的转录因子可能竞争募集有限量的p300。据报道，HPV 16 E6在CH 1、CH 3和C-末端结构域结合p300，而HPV 16 E7结合CH 1和CH 3结构域。由于p300是一种有限的资源，因此很可能HPV 16 E6和HPV 16 E7共同选择宿主p300来控制HPV 16阳性HNSCC细胞中p300的功能。我们的主要假设是宿主p300功能的恢复可能是重新激活p53/pRb和逆转HPV 16诱导的上皮细胞转化的一种方法。在本申请中，生物化学和化学方法将用于探测HPV 16阳性HNSCC中HPV 16 E6/E7和p300之间的相互作用。p300结构域配体的分子作用机制将在体外和体内确定。