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ARID2 modulates DNA damage response in human hepatocellular carcinoma cells.
- Source :
-
Journal of Hepatology . May2017, Vol. 66 Issue 5, p942-951. 10p. - Publication Year :
- 2017
-
Abstract
- 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 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *LIVER cancer
*CANCER cells
*DNA damage
*GENE expression
*GENETIC mutation
Subjects
Details
- Language :
- English
- ISSN :
- 01688278
- Volume :
- 66
- Issue :
- 5
- Database :
- Academic Search Index
- Journal :
- Journal of Hepatology
- Publication Type :
- Academic Journal
- Accession number :
- 122125785
- Full Text :
- https://doi.org/10.1016/j.jhep.2016.12.026