Abstract
BackgroundNormal cells possess a limited proliferative life span after which they enter a state of irreversible growth arrest. This process, known as replicative senescence, is accompanied by changes in gene expression that give rise to a variety of senescence-associated phenotypes. It has been suggested that these gene expression changes result in part from alterations in the histone acetylation machinery. Here we examine the influence of HDAC inhibitors on the expression of senescent markers in pre- and post-senescent WI-38 cells.ResultsPre- and post-senescent WI-38 cells were treated with the HDAC inhibitors butyrate or trichostatin A (TSA). Following HDAC inhibitor treatment, pre-senescent cells increased p21WAF1 and β-galactosidase expression, assumed a flattened senescence-associated morphology, and maintained a lower level of proteasome activity. These alterations also occurred during normal replicative senescence of WI-38 cells, but were not accentuated further by HDAC inhibitors. We also found that HDAC1 levels decline during normal replicative senescence.ConclusionOur findings indicate that HDACs impact numerous phenotypic changes associated with cellular senescence. Reduced HDAC1 expression levels in senescent cells may be an important event in mediating the transition to a senescent phenotype.
Highlights
Normal cells possess a limited proliferative life span after which they enter a state of irreversible growth arrest
histone deacetylase (HDAC) inhibitors induce a senescence-like phenotype in proliferating WI-38 cells HDAC inhibitors can induce growth arrest in many cell types, and have recently been reported to induce a senescence-like state in normal human fibroblasts [26,27]
We sought to determine if the HDAC inhibitors butyrate and trichostatin A (TSA) could induce premature senescence in proliferating WI-38 cells
Summary
Normal cells possess a limited proliferative life span after which they enter a state of irreversible growth arrest. This process, known as replicative senescence, is accompanied by changes in gene expression that give rise to a variety of senescence-associated phenotypes. Normal somatic cells possess a limited proliferative life span after which they enter a state of irreversible growth arrest. This process, known as replicative senescence, can be signaled by shortened telomeres that result from repeated rounds of DNA replication in the absence of telomerase expression. The role of replicative senescence in tumorigenesis is highlighted by the fact that the most common mutations in human cancers occur in genes encoding p53 and members of the pRB pathway, which are the critical effectors of replicative senescence [4,6,7]
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