Oncogenic Chromatin Remodeling and Anticancer Mechanisms

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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.