Oncogenic Chromatin Remodeling and Anticancer Mechanisms

摘要 SWI/SNF染色质重塑复合物赋予表观遗传调节和控制可及性， 染色质到转录机器。染色质重塑在正常生理过程中起重要作用， 疾病，尤其是癌症。ARID 1A是BAF SWI/SNF复合物的组分，是一种主要的肿瘤 抑制器。ARID 1A在广泛的癌症类型中通过体细胞突变失活。尽管 SWI/SNF染色质重塑在癌症中的明显重要性，它们通过生长和致癌调节 信号仍然没有得到很好的理解。mTOR复合物1（mTORC 1）是一种保守的蛋白激酶， 生长控制器mTORC 1是一种致癌驱动因子，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，mTORC 1促进蛋白酶体 ARID 1A蛋白的降解。此外，ARID 1A在治疗反应中起重要作用， 对mTORC 1抑制剂的耐药性。由于mTOR通路估计在所有人类中的近一半中被激活， mTOR依赖性降解是ARID 1A肿瘤的常见机制 抑制基因因此，了解潜在的调控机制及其作用至关重要 在癌症生物学和治疗方面。在本申请中有两个具体目标：目标1将剖析分子 mTORC 1调节ARID 1A和致癌染色质重塑的机制。目标2将调查 mTORC 1依赖性ARID 1A调节在肿瘤发生和抗癌药物应答中的意义。我们 这些研究有望填补ARID 1A肿瘤抑制因子在肿瘤发生中的调节方面的知识空白 和抗癌药物应答/抗性。如果成功，该项目可能会导致针对mTOR的更好战略 路径，改善癌症患者的临床结果。

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.