The role of a histone H4 phosphorylation in drug resistance

组蛋白 H4 磷酸化在耐药性中的作用

• 批准号: 8292471
• 负责人: Zhiguo Zhang
• 金额: $ 32.99万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8292471
• 关键词: Accounting; Address; Alkylating Agents; Brain Neoplasms; Cell Death; Cell Survival; Cells; Chemotherapy-Oncologic Procedure; Clinical Research; DNA; DNA Damage; DNA Methylation; Development; Drug Delivery Systems; Drug resistance; Drug usage; Epigenetic Process; Gene Expression; Gene Expression Regulation; Genes; Glioblastoma; Goals; Guanine; Histone H4; Human; Hypermethylation; Lead; Legal patent; Lesion; Link; Malignant Neoplasms; Mediating; Mismatch Repair; Molecular; Molecular Biology Techniques; Mutation; Newly Diagnosed; Outcome; Patients; Phosphorylation; Phosphotransferases; Positioning Attribute; Primary Brain Neoplasms; Radiation; Reporting; Resistance; Resistance development; Role; Sampling; Serine; Stress; Testing; Therapeutic; Xenograft Model; Xenograft procedure; base; combat; cytotoxic; improved; melanoma; mutant; novel; novel therapeutics; outcome forecast; prevent; promoter; repair enzyme; repaired; response; temozolomide; therapeutic target; tumor progression

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most aggressive form of primary brain tumor in humans. Temozolomide (TMZ) is a critical component of therapy for newly-diagnosed GBM. TMZ is a DNA alkylating agent, methylating the N7 and O6 positions of guanine, and has been used for the treatment of GBM and melanoma. The therapeutic benefit of TMZ depends on its ability to damage DNA and trigger cell death. In addition to cell death, TMZ induced DNA damage can also be repaired, leading to cell survival. The latter outcome results in reduced TMZ efficacy and the development of TMZ resistance. Indeed, almost all GBM patients develop resistance to this drug. Therefore, TMZ resistance is a giant obstacle for the treatment of brain tumors, and it is critically important to determine the molecular mechanisms of acquired TMZ resistance. It is known that O6- methylguanine lesions are repaired by O6-methylguanine-DNA-methytransferase (MGMT); therefore, expression of MGMT confers TMZ resistance. Supporting this idea, multiple clinical studies have indicated that DNA methylation at the MGMT promoter, which results in silencing of MGMT, is associated with prolonged survival of patents receiving both radiation and TMZ treatment. However, even with favorable MGMT promoter hypermethylation, over 40% of patients suffer tumor progression during TMZ therapy, suggesting that mechanisms other than MGMT expression also contribute to TMZ resistance. Our preliminary results indicate that phosphorylation of histone H4 serine 47 (H4S47P) by the Pak2 kinase contributes to the development of TMZ resistance by regulating the expression of MGMT and other genes that confer TMZ resistance. This novel epigenetic mechanism, H4S47P and Pak2-mediated gene regulation, has not been studied in any form of cancer before. Therefore, in this proposal, we will determine how phosphorylation of H4S47 is regulated under TMZ-induced stress, elucidate the molecular mechanisms by which Pak2 and H4S47P contribute to TMZ resistance; and determine to what extent Pak2 and H4S47P levels correlate with the prognosis of primary brain tumors. Together, these studies will reveal a novel epigenetic mechanism by which acquired TMZ resistance is regulated and validate Pak2 as a potential therapeutic target for overcoming TMZ resistance. PUBLIC HEALTH RELEVANCE: Glioblastoma multiforme (GBM), accounting for 52% of all primary brain tumor cases, is the most aggressive type of primary brain tumor. Temozolomide (TMZ) is one of the standard drugs used to treat GBM. However, the efficacy of TMZ is limited by the fact that most patients develop resistance to this drug. Therefore, there is a critical need to address how TMZ resistance is developed. Our preliminary results support the hypothesis that phosphorylation of histone H4 serine 47 (H4S47P) catalyzed by the Pak2 kinase contributes to the development of TMZ resistance in brain tumors. In this proposal, we will employ GBM xenograft models, primary GBM samples and molecular biology techniques to test this hypothesis. These studies will reveal a novel epigenetic mechanism whereby TMZ resistance is developed and potentially identify a novel drug target to combat TMZ resistance, a giant obstacle to successful cancer chemotherapy.

描述（由申请人提供）：多形胶质母细胞瘤（GBM）是人类原发性脑肿瘤最具侵略性的形式。 Temozolomide（TMZ）是新诊断的GBM治疗的关键组成部分。 TMZ是一种DNA烷基化剂，甲基化鸟嘌呤的N7和O6位置，已用于治疗GBM和黑色素瘤。 TMZ的治疗益处取决于其损害DNA和触发细胞死亡的能力。除细胞死亡外，TMZ诱导的DNA损伤也可以修复，从而导致细胞存活。后一个结果导致TMZ功效降低和TMZ抗性的发展。实际上，几乎所有GBM患者都会对这种药物产生抗药性。因此，TMZ耐药性是治疗脑肿瘤的巨大障碍，确定获得的TMZ耐药性的分子机制至关重要。众所周知，O6-甲基鸟嘌呤病变是通过O6-甲基鸟氨酸-DNA-甲基转移酶（MGMT）修复的；因此，MGMT的表达赋予了TMZ抗性。支持这一想法，多项临床研究表明，MGMT启动子的DNA甲基化导致MGMT沉默，与接受放射线和TMZ处理的专利生存期延长有关。然而，即使有良好的MGMT启动子过度甲基化，超过40％的患者在TMZ治疗期间患有肿瘤进展，这表明MGMT表达以外的其他机制也有助于TMZ抗性。我们的初步结果表明，PAK2激酶对组蛋白H4丝氨酸47（H4S47P）的磷酸化通过调节MGMT的表达和其他赋予TMZ抗性的基因来有助于TMZ抗性的发展。这种新型的表观遗传机制H4S47P和PAK2介导的基因调节，以前尚未以任何形式的癌症研究。因此，在此提案中，我们将确定如何在TMZ诱导的应力下调节H4S47的磷酸化，从而阐明PAK2和H4S47P有助于TMZ耐药性的分子机制；并确定PAK2和H4S47P水平在多大程度上与原发性脑肿瘤的预后相关。总之，这些研究将揭示一种新型的表观遗传机制，通过该机制，获得的TMZ耐药性受到调节，并验证PAK2作为克服TMZ耐药性的潜在治疗靶标。 公共卫生相关性：核母细胞瘤（GBM）占所有原发性脑肿瘤病例的52％，是原发性脑肿瘤的最具侵略性类型。替莫唑胺（TMZ）是用于治疗GBM的标准药物之一。但是，TMZ的功效受到大多数患者对该药物的抗性的限制。因此，有急需 解决如何发展TMZ抗性。我们的初步结果支持以下假设：PAK2激酶催化组蛋白H4丝氨酸47（H4S47P）的磷酸化有助于脑肿瘤中TMZ抗性的发展。在此提案中，我们将采用GBM异种移植模型，主要的GBM样品和分子生物学技术来检验该假设。这些研究将揭示出一种新型的表观遗传机制，从而开发了TMZ耐药性，并有可能识别出对抗TMZ耐药性的新型药物靶标，这是成功癌症化学疗法的巨大障碍。