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.

摘要 SWI/SNF染色质重塑复合体具有表观遗传调控作用 染色质到转录机器。染色质重塑在正常生理和免疫反应中起重要作用 疾病，尤其是癌症。ARID1A是BAF SWI/SNF复合体的组成部分，是一种主要的肿瘤 抑制者。ARID1A在广泛的癌症类型中被体细胞突变失活。尽管 SWI/SNF染色质重构体在癌症中的重要性及其对生长和致癌的调节 信号仍然没有被很好地理解。MTOR复合体1(MTORC1)是一种保守的蛋白激酶，是一种中枢蛋白。 增长控制器。MTORC1是致癌驱动因素，也是美国FDA批准的肿瘤药物的靶点 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。因为据估计，在近一半的人类中，mTOR通路被激活 肿瘤，mTOR依赖的降解是ARID1A肿瘤失活的常见机制 癌症的抑制者。因此，重要的是要了解潜在的监管机制及其作用 在癌症生物学和治疗方面。在这一应用中有两个特定的目标：目标1将剖析分子 MTORC1调节ARID1A和致癌染色质重塑的机制。AIM 2将调查 依赖mTORC1的ARID1A调控在肿瘤发生和抗癌药物反应中的意义我们的 研究有望填补ARID1a肿瘤抑制因子在肿瘤发生中的调控知识空白 和抗癌药物反应/耐药性。如果成功，这个项目可能会导致针对mTOR的更好战略 途径，改善癌症患者的临床结果。