Histone deacetylase inhibitors induce a senescence-like state in human cells by a p16-dependent mechanism that is independent of a mitotic clock.
We show here that histone deacetylase inhibitors (HDACIs) sodium dibutyrate (SDB) and trichostatin A (TSA) induce a phenotype that has similarities to replicative senescence in human fibroblasts. There was no evidence that SDB accelerated a constitutive cell division counting mechanism as previously suggested because cells pretreated with SDB for three mean population doublings (MPDs) exhibited a similar overall proliferative life span to controls once SDB was withdrawn. SDB-treated cells upregulated the cell cycle inhibitors p21(WAF1) and p16(INK4A), but not p14(ARF), in the same sequential order as in senescence and the cells developed biochemical markers of senescence. However, the mechanism of senescence did not involve telomere dysfunction and there was no evidence for any posttranslational modification of p53. The expression of human papillomavirus (HPV) 16 E6 in human fibroblasts or targeted disruption of the p53 and p21(WAF) genes only weakly antagonized HDACI-induced senescence. However, expression of the E7 gene, which inhibits the function of pRb, cooperated with E6 to block SDB-induced senescence completely and human cells deficient in p16(INK4A) (but not p14(ARF)) were also resistant to SDB-induced senescence, suggesting that the p16(INK4A)/pRb pathway is the major mediator of HDACI-induced senescence in human cells. However, p53-/- mouse fibroblasts were resistant to HDACI-induced senescence, identifying p53 as the major pathway to senescence in this species.
Munro
June
J
Cancer Research UK Beatson Laboratories, Beatson Institute for Cancer Research, Bearsden, Glasgow, G61 1BD UK.
Barr
Nighean I
NI
Ireland
Hazel
H
Morrison
Vivienne
V
Parkinson
E Kenneth
EK
D000818:Animals; D020148:Butyric Acid / Q000494:pharmacology; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D016922:Cellular Senescence / Q000502:physiology*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency / Q000378:metabolism; D004171:Diploidy; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005333:Fetus; D005347:Fibroblasts / Q000201:enzymology / Q000378:metabolism*; D005786:Gene Expression Regulation; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007621:Karyotyping; D051379:Mice; D027383:Papillomaviridae / Q000378:metabolism; D011233:Precipitin Tests; D016160:Retinoblastoma Protein / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000166:cytology; D013045:Species Specificity; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D016160:Retinoblastoma Protein; D016159:Tumor Suppressor Protein p53; D020148:Butyric Acid; C012589:trichostatin A; D006655:Histone Deacetylases