TY - JOUR
T1 - The role of histone acetylation versus DNA damage in drug-induced senescence and apoptosis
AU - Rebbaa, A.
AU - Zheng, X.
AU - Chu, F.
AU - Mirkin, B. L.
N1 - Funding Information:
This study is supported in part by the National Cancer Institute (1R01 CA096616-01A1 to AR), the Illinois Department of Public Aid (AR), the North Suburban Medical Research Junior Board (AR and BLM), the Anderson Foundation (BLM), the Medical Research Institute Council (BLM), and R Wile Neuroblastoma and Chemotherapy Fund (BLM). We thank Roberta Gerard and Sandra Clark for their assistance in the preparation of this manuscript.
PY - 2006/11
Y1 - 2006/11
N2 - The present study was undertaken to determine the significance of histone acetylation versus DNA damage in drug-induced irreversible growth arrest (senescence) and apoptosis. Cellular treatment with the DNA-damaging drugs doxorubicin and cisplatin or with the histone deacetylase inhibitor trichostatin A, led to the finding that all the three drugs induced senescence at concentrations significantly lower than those required for apoptosis. However, only doxorubicin and cisplatin induced activation of H2AX, a marker for double-strand break formation. Interestingly, this occurred mainly at apoptosis and not senescence-inducing drug concentrations, suggesting that non-DNA-damage pathways may be implicated in induction of senescence by these drugs. In agreement with this, chromatin immunoprecipitation experiments indicated that doxorubicin was able to induce acetylation of histone H3 at the promoter of p21/WAF1 only at senescence-inducing concentrations. Collectively, these findings suggest that alteration of chromatin structure by cytotoxic drugs may represent a key mediator of senescence.
AB - The present study was undertaken to determine the significance of histone acetylation versus DNA damage in drug-induced irreversible growth arrest (senescence) and apoptosis. Cellular treatment with the DNA-damaging drugs doxorubicin and cisplatin or with the histone deacetylase inhibitor trichostatin A, led to the finding that all the three drugs induced senescence at concentrations significantly lower than those required for apoptosis. However, only doxorubicin and cisplatin induced activation of H2AX, a marker for double-strand break formation. Interestingly, this occurred mainly at apoptosis and not senescence-inducing drug concentrations, suggesting that non-DNA-damage pathways may be implicated in induction of senescence by these drugs. In agreement with this, chromatin immunoprecipitation experiments indicated that doxorubicin was able to induce acetylation of histone H3 at the promoter of p21/WAF1 only at senescence-inducing concentrations. Collectively, these findings suggest that alteration of chromatin structure by cytotoxic drugs may represent a key mediator of senescence.
UR - http://www.scopus.com/inward/record.url?scp=33749622817&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=33749622817&partnerID=8YFLogxK
U2 - 10.1038/sj.cdd.4401895
DO - 10.1038/sj.cdd.4401895
M3 - Article
C2 - 16557274
AN - SCOPUS:33749622817
VL - 13
SP - 1960
EP - 1967
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
SN - 1350-9047
IS - 11
ER -