Open AccessHistone deacetylase 2 is involved in DNA damage‐mediated cell death of human osteosarcoma cells through stimulation of the ATM /p53 pathway
Author(s) -
Sun Dan,
Yu Meng,
Li Yuanyuan,
Xing Haotian,
Gao Ying,
Huang Zhihong,
Hao Wenjun,
Lu Kaining,
Kong Chuize,
Shimozato Osamu,
Ozaki Toshinori,
Zhu Yuyan
Publication year - 2019
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12585
Subject(s) - dna damage , histone deacetylase , cancer research , cancer cell , hdac1 , biology , histone , gene knockdown , microbiology and biotechnology , chemistry , apoptosis , cancer , dna , genetics
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 ( HDAC 2) 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 U2 OS cells, and this was accompanied by a remarkable accumulation of p53 and γH2 AX . HDAC 2 gene silencing significantly decreased the sensitivity of U2 OS 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 γH2 AX and cleaved poly (ADP‐ribose) polymerase. However, HDAC 2 knockdown had a marginal effect on p53 ‐null human lung cancer H1299 cells following ADR exposure. In contrast, forced expression of HA ‐ HDAC 2 promoted cell death and stimulated the transcriptional activity of p53. Moreover, p53 and HDAC 2 were found to co‐precipitate with ATM . Together, our present results strongly suggest that the p53– HDAC 2 axis plays a vital role in the regulation of the DNA damage response and also contributes to chemosensitivity of cancer cells.