Histone demethylase JHDM2A participates in the repair of arsenic-induced DNA damage in L-02 cells by regulating DDB2

Abstract

Arsenic is widely present in nature and is a class I carcinogen confirmed by the World Health Organization and the International Agency for Research on Cancer. The liver is responsible for biotransformation in the body and is one of the major organs where arsenic accumulates in the body, but the mechanisms of arsenic-induced abnormal DNA damage repair pathways in the liver are still unclear. Recent studies have revealed that epigenetic mechanisms play an important role in arsenic-induced lesions. In this study, an in vitro model was established using human normal hepatocytes L-02 to investigate the mechanism of the specific demethylase JHDM2A of H3K9me2 in the repair of arsenic-induced DNA damage in L-02 cells. The results showed that with the increase of arsenic concentrations, the extent of DNA damage in L-02 cells showed an increasing trend and total intracellular H3K9me2 expression was downregulated. In addition, the enrichment level of H3K9me2 in the promoter region of DBB2, a key factor of nucleotide repair (NBR), increased, while protein and mRNA expression levels showed a decreasing trend. Thereafter, we overexpressed and repressed JHDM2A and found a close association between JHDM2A and arsenic-induced DNA damage. DDB2 protein and mRNA expression was downregulated with JHDM2A overexpression and upregulated with JHDM2A repression, while DBB2 promoter region H3K9me2 enrichment levels remained at a high level, although they were affected after JHDM2A overexpression or knockdown to some extent. These results suggest a potential mechanism by which JHDM2A may regulate DDB2 gene expression, participate in the NBR process, and play a role in arsenic-induced DNA damage in L-02 cells, which is not the result of JHDM2A exerting demethylation on H3K9me2 in the DDB2 promoter region. Our results provided an epigenetic mechanism for endemic arsenicosis, as well as a scientific basis for potential prevention and control measures.