mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma.

Abstract

The SWI/SNF chromatin remodeling complexes control accessibility of chromatin to transcriptional and coregulatory machineries. Chromatin remodeling plays important roles in normal physiology and diseases, particularly cancer. The ARID1A-containing SWI/SNF complex is commonly mutated and thought to be a key tumor suppressor in hepatocellular carcinoma (HCC), but its regulation in response to oncogenic signals remains poorly understood. mTOR is a conserved central controller of cell growth and an oncogenic driver of HCC. Remarkably, cancer mutations in mTOR and SWI/SNF complex are mutually exclusive in human HCC tumors, suggesting that they share a common oncogenic function. Here, we report that mTOR complex 1 (mTORC1) interact with ARID1A and regulates ubiquitination and proteasomal degradation of ARID1A protein. The mTORC1-ARID1A axis promoted oncogenic chromatin remodeling and YAP-dependent transcription, thereby enhancing liver cancer cell growth <i>in vitro</i> and tumor development <i>in vivo</i>. Conversely, excessive ARID1A expression counteracted AKT-driven liver tumorigenesis <i>in vivo</i>. Moreover, dysregulation of this axis conferred resistance to mTOR-targeted therapies. These findings demonstrate that the ARID1A-SWI/SNF complex is a regulatory target for oncogenic mTOR signaling, which is important for mTORC1-driven hepatocarcinogenesis, with implications for therapeutic interventions in HCC. SIGNIFICANCE: mTOR promotes oncogenic chromatin remodeling by controlling ARID1A degradation, which is important for liver tumorigenesis and response to mTOR- and YAP-targeted therapies in hepatocellular carcinoma.<i>See related commentary by Pease and Fernandez-Zapico, p. 5608</i>.