Induction of tumor suppressor p16INK4A by human papillomavirus 16 E7 oncoprotein

人乳头瘤病毒 16 E7 癌蛋白诱导肿瘤抑制因子 p16INK4A

• 批准号: 8709168
• 负责人: Tyshia Kyree Gwin
• 金额: $ 3.45万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8709168
• 关键词: Affect; Binding; Biological Markers; Bypass; CDK4 gene; CDKN2A gene; Cancer Etiology; Carcinoma; Cell Aging; Cell Cycle Arrest; Cell Death; Cells; Cervical; Cessation of life; Complex; Cyclin D1; Cyclin-Dependent Kinase 4; Cyclin-Dependent Kinase Inhibitor 2A; Development; Epigenetic Process; Epithelial Cells; Event; Excision; Family; Genes; Goals; HPV-High Risk; Histones; Human; Human Papillomavirus; Human papilloma virus infection; Human papillomavirus 16; Individual; Infection; Investigation; Knowledge; Laboratories; Lead; Lesion; Lysine; Malignant Neoplasms; Malignant Vaginal Neoplasm; Malignant neoplasm of anus; Malignant neoplasm of cervix uteri; Malignant neoplasm of penis; Malignant neoplasm of vulva; Modality; Modeling; Molecular; Mutation; Oncogene Activation; Oncogene Proteins; Oncogenes; Oncogenic; Oropharyngeal; Pathway interactions; Polycomb; Proliferating; Proteins; Publications; Publishing; Reporting; Repression; Research; Retinoblastoma Protein; Signal Transduction; Stress; Testing; Therapeutic; Transcriptional Activation; Tumor Suppressor Genes; Tumor Suppressor Proteins; Vaccines; Woman; Work; base; cancer type; effective therapy; inhibitor/antagonist; insight; mutant; prevent; promoter; public health relevance; response; retinoblastoma tumor suppressor; senescence; small molecule; therapeutic target; tumor; young woman

High-risk human papillomavirus (HPV) infections are associated with a variety of carcinomas including oropharyngeal, cervical, vulvar, vaginal, anal, and penile cancers. Over 99% of cervical cancers, which are the most common cause of cancer death in young women, are associated with high-risk HPV infections. Although there are effective vaccines against the two most common cancer causing high-risk HPV types, the vaccines only protect against new infections. For this reason, efforts into HPV research to develop effective therapies are critical to treat effected individuals, which is the ultimate goal of the work in this proposal. High-risk HPV type 16 infection results in the induction of the tumor suppressor p16INK4A as a consequence of the expression of the E7 oncoprotein. Normally, the p16INK4A protein inhibits cyclin dependent kinases (CDK) 4/6 leading to an accumulation of the hypophosphorylated form of the retinoblastoma tumor suppressor pRB which results in cellular senescence; however, HPV16 positive cells continue to proliferate since the HPV E7 protein also subverts senescence through the binding and degradation of pRB. This proposal seeks to bridge the gap in knowledge by determining cellular pathways that are dysregulated by E7 leading to oncogenic stress and induction of p16INK4A. It is known that E7 expression results in the induction of the histone 3 lysine 27 (H3K27) demethylase KDM6B, which removes repressive trimethylation marks on polycomb repressed genes including p16INK4A. Removal of a single repressive mark does not necessarily render a gene transcriptionally active, and it is unknown if E7 expression changes the core set of histone marks that need to be altered when a polycomb repressed gene is activated. The second goal of this proposal is to elucidate these changes using the p16INK4A promoter as a model gene under polycomb repression because p16INK4A serves as a biomarker for HPV- associated cancers and is an important tumor suppressor that triggers oncogene-induced senescence. Moreover, our lab has demonstrated that E7 expressing cells are epigenetically reprogrammed and become "addicted" to expression of p16INK4A and KDM6B and promising preliminary investigations with a small molecule inhibitor of KDM6B demonstrate decreased proliferation/survival of E7 expressing cells. Therefore, identification of other epigenetic factors that regulate p16INK4A expression may provide insight into additional potential therapeutic modalities that can be tested. As several other cancers also have increased levels of p16INK4A, these results may be applicable to the treatment of other non-HPV associated cancers.

高危人乳头瘤病毒（HPV）感染与多种癌症有关，包括 口咽癌、宫颈癌、外阴癌、阴道癌、肛门癌和阴茎癌。超过99%的宫颈癌， 年轻女性癌症死亡的最常见原因，与高危HPV感染有关。虽然 有针对两种最常见的导致高风险HPV类型的癌症的有效疫苗， 只保护免受新的感染。出于这个原因，努力进行HPV研究，以开发有效的治疗方法， 对于治疗受影响的个人至关重要，这是本提案工作的最终目标。高危型HPV 16型感染导致肿瘤抑制因子p16 INK 4A的诱导， E7癌蛋白正常情况下，p16 INK 4A蛋白抑制细胞周期蛋白依赖性激酶（CDK）4/6，从而导致细胞周期蛋白依赖性激酶（CDK）4/6。 视网膜母细胞瘤肿瘤抑制因子pRB的低磷酸化形式的积累， 细胞衰老;然而，HPV 16阳性细胞继续增殖，因为HPV E7蛋白也 通过pRB的结合和降解破坏衰老。这项建议旨在弥合以下方面的差距： 通过确定由E7失调导致致癌应激的细胞途径来了解， p16 INK 4A的诱导。已知E7表达导致组蛋白3赖氨酸27（H3 K27）的诱导， 脱甲基酶KDM 6 B，其去除多梳抑制基因上的抑制性三甲基化标记，包括 p16INK4A。去除单个抑制标记并不一定使基因转录活跃，并且 目前尚不清楚E7的表达是否改变了组蛋白标记的核心组，而当多梳蛋白表达时， 被抑制的基因被激活。该提案的第二个目标是使用p16 INK 4A来阐明这些变化。 启动子作为多梳抑制下的模型基因，因为p16 INK 4A作为HPV的生物标志物- 是一种重要的肿瘤抑制因子，可触发癌基因诱导的衰老。 此外，我们的实验室已经证明，表达E7的细胞被表观遗传学重编程，并成为 对p16 INK 4A和KDM 6 B的表达“上瘾”，并对小分子进行了有希望的初步研究 KDM 6 B抑制剂显示E7表达细胞的增殖/存活降低。因此，我们认为， 鉴定调节p16 INK 4A表达的其他表观遗传因子可以提供对其他基因的了解。 可以测试的潜在治疗模式。由于其他几种癌症也有增加的水平， p16 INK 4A，这些结果可能适用于其他非HPV相关癌症的治疗。