H3K9 Methylation and Pancreatic Cancer Chemoresistance

H3K9 甲基化与胰腺癌化疗耐药

• 批准号: 8692271
• 负责人: KEBIN LIU
• 金额: $ 19.69万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-04 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8692271
• 关键词: Agaricales; American Cancer Society; Apoptosis; Cancer Patient; Cells; Cessation of life; Colorectal Cancer; Development; Diagnosis; Disease; Dose; Epigenetic Process; Gene Expression; Gene Targeting; Genetic Transcription; Growth; Histone H3; Human; In Vitro; Induction of Apoptosis; Legal patent; Lysine; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Methylation; Molecular Target; Pancreas; Patients; Pharmaceutical Preparations; Regulator Genes; Resistance; Survival Rate; Technology; Testing; Therapeutic Agents; Time; Transcriptional Activation; advanced disease; cancer cell; cancer therapy; effective therapy; gemcitabine; gene function; genome-wide; histone methyltransferase; in vivo; inhibitor/antagonist; novel; pancreatic cancer cells; pathogen; promoter; public health relevance; verticillin A

DESCRIPTION (provided by applicant): Pancreatic cancer is a death sentence for patients diagnosed with this disease, as there are few effective treatments. Gemcitabine is currently the standard therapy for human pancreatic cancer patients. However, gemcitabine only increases survival rate of human pancreatic cancer patients with advanced disease by a medium time of 5 weeks since human pancreatic cancer cells are often resistant to gemcitabine. Therefore, development of novel agent that can overcome pancreatic cancer resistance to gemcitabine is in urgent need. We have recently discovered that a natural compound (verticillin A) purified from pathogen-infected wild mushrooms can effectively overcome resistance of human cancers to therapeutic agents both in vitro and in vivo. We have now identified the molecular target of verticillin A: Verticillin A is a specific inhibitor of histone methyltransferases (HMTases) SUV39H1, SUV39H2, G9a and GLP, all of which catalyze methylation of lysine 9 of histone H3 (H3K9). Verticillin A inhibits these HMTases to de-methylate H3K9me2 and H3K9me3, resulting in transcriptional activation of epigenetically silenced apoptosis-regulatory genes and sensitization of human cancer cells to apoptosis- inducing therapeutic agents. Importantly, we observed that verticillin A is extremely effective in sensitization of human pancreatic cancer cell to gemcitabine-mediated growth inhibition in vitro. The objective of this project is to elucidate te mechanism of verticillin A action in human pancreatic cancer cells and to determine the efficacy of verticillin A in vivo. Our hypothesis is that verticillin A inhibits H3K9 methylation to reactivte transcription of epigenetically silenced apoptosis regulatory genes to sensitize human pancreatic cancer cell to gemcitabine-induced apoptosis. To test this hypothesis, we will pursue 2 specific aims: 1) test the hypothesis that verticillin A overcomes human pancreatic cancer resistance to gemcitabine through inhibition of H3K9 methylation to activate transcription of apoptosis regulatory genes; and 2) determine the efficacy of verticillin A in overcoming pancreatic cancer resistance to standard chemotherapeutics in vivo. Successful completion of the proposed studies has the potential to develop verticlillin A as an adjunct agent to overcome pancreatic cancer resistance to gemcitabine in human cancer therapy.

描述(申请人提供)：胰腺癌是被诊断为这种疾病的患者的死刑，因为几乎没有有效的治疗方法。吉西他滨目前是人类胰腺癌患者的标准治疗方法。然而，由于人胰腺癌细胞往往对吉西他滨具有耐药性，吉西他滨仅能将晚期胰腺癌患者的存活率提高5周。因此，迫切需要开发新的药物来克服胰腺癌对吉西他滨的耐药性。我们最近发现，从病原体感染的野生蘑菇中提纯的一种天然化合物(轮枝菌素A)，在体内外都能有效地克服人类癌症对治疗药物的耐药性。我们现在已经确定了轮枝菌素A的分子靶点：轮枝菌素A是组蛋白甲基转移酶SUV39H1、SUV39H2、G9a和GLP的特异性抑制剂，所有这些酶都催化组蛋白H3(H3K9)赖氨酸9的甲基化。轮枝菌素A抑制这些HMTase去甲基化H3K9me2和H3K9me3，导致表观沉默的凋亡调节基因的转录激活，并使人类癌细胞对诱导凋亡的治疗药物敏感。重要的是，我们观察到维替西林A在体外非常有效地增敏人胰腺癌细胞对吉西他滨介导的生长抑制。本课题的目的是阐明维替西林A在人胰腺癌细胞中的作用机制，并确定其体内的作用效果。我们的假设是，维替西林A抑制H3K9甲基化，激活表观遗传沉默的凋亡调控基因的转录，从而使人胰腺癌细胞对吉西他滨诱导的凋亡敏感。为了验证这一假设，我们将追求两个具体目标：1)测试垂直青霉素A通过抑制H3K9甲基化激活细胞凋亡调控基因转录来克服胰腺癌对吉西他滨耐药的假设；以及2)在体内确定垂直霉素A在克服胰腺癌对标准化疗药物的耐药性方面的有效性。拟议研究的成功完成有可能开发出垂直氯西林A作为辅助药物，在人类癌症治疗中克服胰腺癌对吉西他滨的耐药性。