The role of histone acetylation versus DNA damage in drug-induced senescence and apoptosis.
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.
Children's Memorial Research Center, Children's Memorial Hospital, Department of Pediatrics, Northwestern University, Chicago, IL 60614, USA. arebbaa@childrensmemorial.org
A
A
Rebbaa
X
X
Zheng
F
F
Chu
B L
BL
Mirkin
D000107:Acetylation / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D016922:Cellular Senescence / Q000187:drug effects*; D002945:Cisplatin / Q000494:pharmacology*; D020552:Comet Assay; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D006657:Histones / Q000378:metabolism*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007700:Kinetics; D015203:Reproducibility of Results; D013997:Time Factors
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C468783:H2AX protein, human; D006657:Histones; D006877:Hydroxamic Acids; C012589:trichostatin A; D004317:Doxorubicin; D004247:DNA; D002945:Cisplatin