mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma

Zhang, Shanshan; Zhou, Yu-Feng; Cao, Jian; Burley, Stephen K.; Wang, Hui-Yun; Zheng, X. F.  Steven

doi:10.1158/0008-5472.can-21-0206

mTORC1 Promotes ARID1A Degradation and Oncogenic Chromatin Remodeling in Hepatocellular Carcinoma

Journal Article · 24 August 2021 · Cancer Research

DOI:https://doi.org/10.1158/0008-5472.can-21-0206· OSTI ID:1980902

Zhang, Shanshan; Zhou, Yu-Feng; ; ; ; Zheng, X. F. Steven

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

Research Organization:: Rutgers Univ., Piscataway, NJ (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

DOE Contract Number:: SC0019749

OSTI ID:: 1980902

Journal Information:: Cancer Research, Vol. 81, Issue 22; ISSN 0008-5472

Publisher:: American Association for Cancer Research

Country of Publication:: United States

Language:: English

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