ARID2 modulates DNA damage response in human hepatocellular carcinoma cells

作者：Oba Atsushi; Shimada Shu; Akiyama Yoshimitsu; Nishikawaji Taketo; Mogushi Kaoru; Ito Hiromitsu; Matsumura Satoshi; Aihara Arihiro; Mitsunori Yusuke; Ban Daisuke; Ochiai Takanori; Kudo Atsushi; Asahara Hiroshi; Kaida Atsushi; Miura Masahiko; Tanabe Minoru; Tanaka Shinji

来源：Journal of Hepatology, 2017, 66(5): 942-951.

DOI：10.1016/j.jhep.2016.12.026

• Hepatocellular carcinoma
• ARID2
• DNA damage response
• Nucleotide excision repair
• SWI/SNF
• XPC
• CRISPR/Cas9
• XPG
• Benzo[a]pyrene

Background & Aims: 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.
Methods: We established the ARID2 knockout human HCC cell lines by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions.
Results: 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.
Conclusions: 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.
Lay summary: Recent genomic studies have identified frequent mutations of ARID2, a component of the SWItch/Sucrose NonFermentable (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.

• 出版日期2017-5