Abstract
Tumor suppressor p53 is a short-lived nuclear transcription factor, which becomes stabilized and activated in response to a wide variety of cellular stresses. Around 50% of human cancer tissues carry p53 mutations, and certain p53 mutations contribute to chemoresistance. In the present study, we found that histone deacetylase 2 (HDAC2) acts as a co-activator of tumor suppressor p53 and participates in the early molecular events following DNA damage. Anti-cancer drug adriamycin (ADR) treatment induced cell death in p53-wild-type human osteosarcoma U2OS cells, and this was accompanied by a remarkable accumulation of p53 and γH2AX. HDAC2 gene silencing significantly decreased the sensitivity of U2OS cells to ADR and attenuated p53-dependent DNA damage responses, such as ADR-mediated phosphorylation of ataxia telangiectasia mutated (ATM) and p53, as well as accumulation of γH2AX and cleaved poly (ADP-ribose) polymerase. However, HDAC2 knockdown had a marginal effect on p53-null human lung cancer H1299 cells following ADR exposure. In contrast, forced expression of HA-HDAC2 promoted cell death and stimulated the transcriptional activity of p53. Moreover, p53 and HDAC2 were found to co-precipitate with ATM. Together, our present results strongly suggest that the p53-HDAC2 axis plays a vital role in the regulation of the DNA damage response and also contributes to chemosensitivity of cancer cells.