Oncogenic Chromatin Remodeling and Anticancer Mechanisms

致癌染色质重塑和抗癌机制

• 批准号: 10646923
• 负责人: STEVEN ZHENG
• 金额: $ 45.31万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-08 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10646923
• 关键词: ARID1A gene; Antineoplastic Agents; CCI-779; Cancer Biology; Cancer Patient; Chromatin; Chromatin Remodeling Factor; Clinical; Complex; Data; Development; Disease; FDA approved; FRAP1 gene; Genetic Transcription; Growth; Human; Knowledge; Lead; Malignant Neoplasms; Mediating; Molecular; Oncogenic; Oncology; Outcome; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiology; Play; Protein Kinase; Proteins; Publishing; Regulation; Resistance; Role; SWI/SNF Family Complex; Serine; Signal Pathway; Signal Transduction; Sirolimus; Somatic Mutation; Testing; Therapeutic; Tumor Suppressor Proteins; anti-cancer; cancer therapy; cancer type; chromatin remodeling; epigenetic regulation; improved; in vivo; inhibitor; public health relevance; response; targeted cancer therapy; targeted treatment; therapy resistant; treatment response; tumor; tumorigenesis

ABSTRACT The SWI/SNF chromatin remodeling complexes impart epigenetic regulation and control accessibility of chromatin to transcriptional machineries. Chromatin remodeling plays important roles in normal physiology and diseases, particularly cancer. ARID1A is a component of the BAF SWI/SNF complex and a major tumor suppressor. ARID1A is inactivated by somatic mutations in a wide spectrum of cancer types. Despite the apparent importance of SWI/SNF chromatin remodelers in cancer, their regulation by growth and oncogenic signals remains not well understood. mTOR complex 1 (mTORC1) is a conserved protein kinase and a central growth controller. mTORC1 is an oncogenic driver and the target of US FDA-approved oncology drugs rapamycin and rapamycin analogs. Our preliminary data revealed that mTORC1 promotes proteasomal degradation of ARID1A protein. Moreover, ARID1A plays an important role in therapeutic response and resistance to mTORC1 inhibitors. Because mTOR pathway is estimated to be activated in nearly half of all human tumors, mTOR-dependent degradation represents a common mechanism to inactivate the ARID1A tumor suppressor in cancer. Therefore, it is important to understand the underlying regulatory mechanisms and its role in cancer biology and therapy. There are two specific aims in this application: Aim 1 will dissect the molecular mechanism by which mTORC1 regulates ARID1A and oncogenic chromatin remodeling. Aim 2 will investigate the significance of mTORC1-dependent ARID1A regulation in tumorigenesis and anticancer drug response. Our studies are anticipated to fill a knowledge gap in the regulation of the ARID1A tumor suppressor in tumorigenesis and anticancer drug response/resistance. If successful, this project could lead to better strategies to target mTOR pathway, improving clinical outcomes for cancer patients.

抽象的 SWI/SNF 染色质重塑复合物赋予表观遗传调控并控制染色质的可及性 染色质到转录机器。染色质重塑在正常生理和 疾病，特别是癌症。 ARID1A 是 BAF SWI/SNF 复合体的组成部分，也是一种主要肿瘤 抑制器。 ARID1A 在多种癌症类型中会因体细胞突变而失活。尽管 SWI/SNF 染色质重塑剂在癌症中的明显重要性及其对生长和致癌的调节 信号仍然没有得到很好的理解。 mTOR 复合物 1 (mTORC1) 是一种保守的蛋白激酶， 生长控制器。 mTORC1 是一种致癌驱动因素，也是美国 FDA 批准的肿瘤药物的靶标 雷帕霉素和雷帕霉素类似物。我们的初步数据显示 mTORC1 促进蛋白酶体 ARID1A 蛋白的降解。此外，ARID1A 在治疗反应和 对 mTORC1 抑制剂的耐药性。因为 mTOR 通路估计在近一半的人类中被激活 肿瘤中，mTOR 依赖性降解代表了 ARID1A 肿瘤失活的常见机制 癌症中的抑制剂。因此，了解潜在的监管机制及其作用非常重要 在癌症生物学和治疗方面。此应用程序有两个具体目标： 目标 1 将剖析分子 mTORC1 调节 ARID1A 和致癌染色质重塑的机制。目标 2 将进行调查 mTORC1 依赖性 ARID1A 调节在肿瘤发生和抗癌药物反应中的重要性。我们的 研究预计将填补 ARID1A 肿瘤抑制因子在肿瘤发生中调节的知识空白 和抗癌药物反应/耐药性。如果成功，该项目可能会带来更好的针对 mTOR 的策略 途径，改善癌症患者的临床结果。