Histone deacetylase 2 is involved in DNA damage-mediated cell death of human osteosarcoma cells through stimulation of the ATM/p53 pathway.

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.