title: ARID2 modulates DNA damage response in human hepatocellular carcinoma cells.
abstract: Recent genomic studies have identified frequent mutations of AT-rich interactive domain 2 (ARID2) in hepatocellular carcinoma (HCC), but it is not still understood how ARID2 exhibits tumor suppressor activities.
  
  
  
  We established the ARID2 knockout human HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions.
  
  
  
  Bioinformatic analysis indicated that UV-response genes were negatively regulated in the ARID2 knockout cells, and they were sensitized to UV irradiation. ARID2 depletion attenuated nucleotide excision repair (NER) of DNA damage sites introduced by exposure to UV as well as chemical compounds known as carcinogens for HCC, benzo[a]pyrene and FeCl3, since xeroderma pigmentosum complementation group G (XPG) could not accumulate without ARID2. By using large-scale public data sets, we validated that ARID2 knockout could lead to similar molecular changes between in vitro and in vivo settings. A higher number of somatic mutations in the ARID2-mutated subtypes than that in the ARID2 wild-type across various types of cancers including HCC was observed.
  
  
  
  We provide evidence that ARID2 knockout could contribute to disruption of NER process through inhibiting the recruitment of XPG, resulting in susceptibility to carcinogens and potential hypermutation. These findings have implications for therapeutic targets in cancers harboring ARID2 mutations.
  
  
  
  Recent genomic studies have identified frequent mutations of ARID2, a component of the SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, in hepatocellular carcinoma, but it is not still understood how ARID2 exhibits tumor suppressor activities. In current study, we provided evidence that ARID2 knockout could contribute to disruption of DNA repair process, resulting in susceptibility to carcinogens and potential hypermutation. These findings have far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations.
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Oba
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shu
authors.initials: S
authors.lastname: Shimada
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yoshimitsu
authors.initials: Y
authors.lastname: Akiyama
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Taketo
authors.initials: T
authors.lastname: Nishikawaji
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Mogushi
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Ito
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Matsumura
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Arihiro
authors.initials: A
authors.lastname: Aihara
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Mitsunori
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Daisuke
authors.initials: D
authors.lastname: Ban
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Takanori
authors.initials: T
authors.lastname: Ochiai
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kudo
authors.affiliation: Department of Systems Biomedicine, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Asahara
authors.affiliation: Department of Oral Health Sciences, Graduate School of Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kaida
authors.affiliation: Department of Oral Health Sciences, Graduate School of Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Miura
authors.affiliation: Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Tanabe
authors.affiliation: Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan; Department of Hepato-Biliary-Pancreatic Surgery, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: tanaka.monc@tmd.ac.jp.
authors.forename: Shinji
authors.initials: S
authors.lastname: Tanaka
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D045744:Cell Line, Tumor; D019295:Computational Biology; D004249:DNA Damage; D004260:DNA Repair; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D009154:Mutation; D017382:Reactive Oxygen Species / Q000378:metabolism; D014157:Transcription Factors / Q000502:physiology*; D014466:Ultraviolet Rays
chemical_list: C512511:ARID2 protein, human; D017382:Reactive Oxygen Species; D014157:Transcription Factors
keywords: ARID2; Benzo[a]pyrene; CRISPR/Cas9; DNA damage response; Hepatocellular carcinoma; Nucleotide excision repair; SWI/SNF; XPC; XPG