1. mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma
- Author
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X. F.Steven Zheng, Shanshan Zhang, Stephen K. Burley, Jian Cao, Hui-Yun Wang, and Yu-Feng Zhou
- Subjects
Male ,Cancer Research ,Carcinoma, Hepatocellular ,ARID1A ,Apoptosis ,Cell Cycle Proteins ,mTORC1 ,Mechanistic Target of Rapamycin Complex 1 ,Chromatin remodeling ,Mice ,Ubiquitin ,Biomarkers, Tumor ,Tumor Cells, Cultured ,medicine ,Animals ,Humans ,PI3K/AKT/mTOR pathway ,Cell Proliferation ,biology ,Cell growth ,TOR Serine-Threonine Kinases ,Liver Neoplasms ,Ubiquitination ,Cancer ,Chromatin Assembly and Disassembly ,Prognosis ,medicine.disease ,Xenograft Model Antitumor Assays ,Chromatin ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,Survival Rate ,Oncology ,Mutation ,Proteolysis ,biology.protein ,Cancer research ,biological phenomena, cell phenomena, and immunity ,Transcription Factors - 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 in vitro and tumor development in vivo. Conversely, excessive ARID1A expression counteracted AKT-driven liver tumorigenesis in vivo. 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. See related commentary by Pease and Fernandez-Zapico, p. 5608
- Published
- 2021