Disruption of DNA damage response by ARID2 knockout in human hepatocellular carcinoma cells

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 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-KO cells, and they were certainly 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 XPG could not be accumulated 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, and moreover observed 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. Conclusions: We provided 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 far-reaching implications for therapeutic targets in cancers harboring ARID2 mutations. We established the ARID2 knockout HCC cell lines (JHH4 and JHH5) by using CRISPR/Cas9 system, and investigated the gene expression profiles and biological functions.