Enhancing chemotherapy sensitivity by targeting PcG via the ATM/p53 pathway

Histone modification and chromatin remodeling are important events in response to DNA damage, and Polycomb group (PcG) proteins, catalyzing H3K27 methylation, are involved. However, the biological function and mechanism of PcG in DNA damage are not fully understood. Additionally, downstream effectors in hepatocellular carcinoma (HCC) remain unclear. The present study investigated the biological and mechanistic roles of PcG in the DNA damage response induced by chemotherapeutic drugs in HCC. It was found that chemotherapy drugs, such as epirubicin (EPB) and mitomycin C (MMC), effectively blocked expression of PcG in p53-wild-type HepG2 cells but not in PLC/PRF5 and Hep3B cells with p53 mutation or deletion. PcG-related target genes involved in DNA damage were identified, including p53, Ataxia telangiectasia mutated (ATM) and Forkhead box O3 (FOXO3). Moreover, targeting PcG-induced p53 expression was associated with increased drug sensitivity in HCC cells. shRNA targeting enhancer of zeste homolog 2 (EZH2) or its inhibitor GSK126 significantly promoted chemotherapeutic drug-induced genotoxicity and increased HepG2 cell chemosensitivity. Mechanistically, chromatin immunoprecipitation (ChIP) assays confirmed that PcG binds to the ATM promoter and inhibits its expression through covalent modification of H3K27me3. Herein, we establish a potential chemotherapy association with GSK126, and the findings suggest this link might represent a new strategy for increasing the sensitivity of HCC to chemotherapeutic agents.