H3K9 Methylation and Pancreatic Cancer Chemoresistance

描述（由申请人提供）：胰腺癌对于被诊断患有这种疾病的患者来说是死刑判决，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药物。然而，吉西他滨仅能提高人类胰腺癌晚期患者5周的生存率，因为人类胰腺癌细胞通常对吉西他滨具有耐药性。因此，迫切需要开发能够克服胰腺癌对吉西他滨耐药的新型药物。我们最近发现，从感染病原体的野生蘑菇中纯化的天然化合物（verticillin a）可以在体外和体内有效地克服人类癌症对治疗剂的耐药性。我们现在已经确定了verticillin A的分子靶点：verticillin A是组蛋白甲基转移酶（HMTases） SUV39H1、SUV39H2、G9a和GLP的特异性抑制剂，它们都能催化组蛋白H3 （H3K9）赖氨酸9的甲基化。Verticillin A抑制这些hmtase，使H3K9me2和H3K9me3去甲基化，导致表观遗传沉默的凋亡调控基因转录激活，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verticillin A在体外对吉西他滨介导的生长抑制的人胰腺癌细胞敏化方面非常有效。本项目旨在阐明verticillin A在人胰腺癌细胞中的作用机制，并确定verticillin A在体内的作用效果。我们的假设是，verticillin A抑制H3K9甲基化，从而激活表观遗传沉默的凋亡调节基因的转录，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，我们将追求两个特定的目标：1)验证verticillin A通过抑制H3K9甲基化激活凋亡调节基因的转录来克服人类胰腺癌对吉西他滨的耐药性的假设；2)确定verticillin A在体内克服胰腺癌对标准化疗药物耐药的疗效。该研究的成功完成有潜力开发垂直青霉素A作为辅助药物，以克服胰腺癌在人类癌症治疗中对吉西他滨的耐药性。

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.