In the present study, we have found that HDAC2 gene silencing attenuates the ATM/p53‐mediated cell death pathway of osteosarcoma U2OS cells in response to ADR, indicating that HDAC2 participates in the early molecular events of DNA damage response, and also acts as a co‐activator of p53. The gene discussed is TP53; the disease is osteosarcoma.