Chromatin remodeling gene<i>ARID2</i>targets cyclin D1 and cyclin E1 to suppress hepatoma cell progression

Abstract

// Yujie Duan 1, * , Ling Tian 1, * , Qingzhu Gao 1, * , Li Liang 1 , Wenlu Zhang 1 , Yi Yang 1 , Yaqiu Zheng 1 , E Pan 1 , Shengwei Li 1 , Ni Tang 1 1 Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), Institute for Viral Hepatitis, Department of Infectious Diseases, The Second Affiliated Hospital, Chongqing Medical University, Chongqing, PR China * These authors contributed equally to this work Correspondence to: Shengwei Li, email: lishengwei11@163.com Ni Tang, email: nitang@cqmu.edu.cn Keywords: ARID2, SWI/SNF complex, the Rb/E2F pathway, hepatocellular carcinoma, cell-cycle arrest Received: March 02, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Accepted: June 03, 2016&nbsp;&nbsp;&nbsp;&nbsp;&nbsp; Published: June 23, 2016 ABSTRACT Exome and whole-genome sequencing studies have drawn attention to the role of somatic mutations in SWI/SNF chromatin remodeling complexes in the carcinogenesis of hepatocellular carcinoma (HCC). Here, we explored the molecular mechanisms underlying the biological roles of AT-rich interactive domain 2 (ARID2) in the pathogenesis of HCC. We found that ARID2 expression was significantly downregulated in HCC tissues compared with non-tumorous tissues. Restoration of ARID2 expression in hepatoma cells was sufficient to suppress cell proliferation and tumor growth in mice, whereas ARID2 knockdown contributed to the enhancement of cellular proliferation and tumorigenicity. Suppression of ARID2 expression accelerated G1/S transition associated with upregulation of cyclin D1, cyclin E1, CDK4, and phosphorylation of the retinoblastoma protein (Rb). Furthermore, we demonstrated that ARID2 physically interacts with E2F1 and decreases binding of E2F1/RNA Pol II to the promoters of CCND1 and CCNE1 . Taken together, these results demonstrate that ARID2 suppresses tumor cell growth through repression of cyclin D1 and cyclin E1 expression, thereby retarding cell cycle progression and cell proliferation in hepatoma cells. These findings highlight the potential role of ARID2 as a tumor growth suppressor in HCC.