Role of p300 in HPV-positive Head and Neck Cancer

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），特别是口咽鳞状细胞癌的主要危险因素的认识。高危型HPV16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，在美国和欧洲，hpv阳性HNSCC的患病率在过去三十年中迅速增加了约3倍（2-4）。基于这些令人震惊的数字，有人认为hpv阳性的HNSCC将在不久的将来出现流行。需要进一步的工作来探索hpv诱导肿瘤发生的作用机制，以揭示可操作的“可药物”靶点，以开发hpv导向的抗癌治疗方法。P300是一种转录共激活因子，通过多种机制控制基因转录；作为组蛋白和转录因子乙酰化的乙酰转移酶，作为转录因子在染色质上的支架，作为连接转录因子与转录机制的桥梁。有趣的是，p300的单等位基因敲除具有不同的转录表型，这表明启动子结合的转录因子可能在竞争中招募有限数量的p300。据报道，HPV16E6与p300在CH1、CH3和c端结合，而HPV16E7与CH1和CH3结合。由于p300是一种有限的资源，HPV16E6和HPV16E7可能会协同宿主p300来控制hpv16阳性HNSCC细胞中p300的功能。我们的主要假设是，恢复宿主p300功能可能是一种重新激活p53/pRb和逆转hpv16诱导的上皮细胞转化的方法。在本应用中，将采用生化和化学方法来探讨HPV16E6/E7和p300在hpv16阳性HNSCC中的相互作用。p300结构域配体的分子作用机制将在体内和体外得到明确。

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.