HDACs and the senescent phenotype of WI-38 cells
© Place et al; licensee BioMed Central Ltd. 2005
Received: 08 June 2005
Accepted: 26 October 2005
Published: 26 October 2005
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. 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.
Pre- 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.
Our 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.
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. Once the telomeres erode to an average size of 4–6 kilobases, senescence is triggered and cells stop dividing [1, 2]. Replicative senescence plays an important role in maintaining the structural integrity of tissues by limiting the excessive clonal expansion of cells [3, 4]. However, the accumulation of senescent cells is also believed to contribute to the age-related decline in tissue function . Replicative senescence can therefore be viewed as both a mechanism of tumor suppression and a contributor in pathologies associated with age. 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].
A number of fundamental metabolic and biochemical changes occur as a cell enters senescence and begins to age. Numerous studies have reported dramatic changes in protein turnover. The proteasome, the primary non-lysosomal protease responsible for degrading intracellular proteins including misfolded, oxidized and ubiquitinated proteins, has been reported to decline in function with age [8–13]. Several reports have indicated that the expression of certain proteasome subunits drops after cells enter replicative senescence [14–17]. In addition, proteasome inhibition, or "clogging", has been observed as aging cells accumulate damaged proteins [12, 13, 18]. The resulting drop in protein turnover may contribute to the accumulation of protein deposits, such as lipofuscin, which can further compromise cell function . In addition, the drop in proteasome activity is likely to alter the activity of numerous cellular signal transduction pathways that involve the proteasome.
Replicative senescence is accompanied by many changes in gene expression that contribute to the senescence-associated phenotypes. Of particular importance are the cell cycle inhibitors p16INK4a and p21WAF1, which are induced upon replicative senescence to halt cell proliferation [20, 21]. Interestingly, many genes involved in the regulation of cellular growth arrest and differentiation are regulated by histone acetylation. For example, in proliferating fibroblasts, the stable association of HDAC1 with the Sp1/Sp3 transcription factors bound to the p21WAF1 promoter suppresses p21WAF1 expression. Upon senescence, HDAC1 is displaced from to the p21WAF1 promoter, due in part to the actions of p53 .
HDAC inhibitors have long been known to induce differentiation, growth arrest, and apoptosis in cancer cells [23–25]. The aberrant utilization of HDACs is believed to be a contributing factor in carcinogenesis. However, only recently have HDAC inhibitors been shown to induce premature senescence in normal human fibroblasts [26, 27]. HDACs may therefore play a critical role in modulating cell physiology during the aging process, as well as contribute to the cellular changes associated with transformation. Here we examine the interplay between cellular HDAC activity and a number of phenotypic changes that accompany cell senescence. We find that replicative senescence is accompanied by a drop in cellular HDAC1 expression, the activation of the cell cycle inhibitory protein p21WAF1, and a reduction in cellular proteasome activity and subunit expression. The critical role of HDACs in regulating these events is supported by the finding that HDAC inhibitors selectively trigger these changes in pre-senescent, but not post-senescent cells. Our findings indicate that a drop in HDAC expression may be a critical event in mediating the transition from a proliferating to a senescent phenotype.
HDAC inhibitors induce a senescence-like phenotype in proliferating WI-38 cells
Proteasome activity is reduced in senescent WI-38 cells
Senescent WI-38 cells are resistant to HDAC inhibitors
HDAC inhibitors have also been reported to suppress proteasome activity and subunit expression in several transformed cell lines [33–35]. We hypothesized that HDAC inhibitors may suppress proteasome activity in proliferating WI-38 cells, as well. Cytosolic extracts were prepared from young WI-38 cells treated with butyrate or TSA for 0, 24, 48, and 72 hours. The synthetic substrate Suc-LLVY-AMC was then utilized to measure proteasome activity in each sample. As shown in Figure 6B, proteasome activity decreased in young WI-38 cells treated with either butyrate or TSA. To determine if senescent WI-38 cells were also sensitive to HDAC inhibitor-induced proteasome suppression, the proteasome activity of senescent WI-38 cells was analyzed following butyrate or TSA treatment. Although proteasome activity was lower in senescent WI-38 cells (as shown in Figure 3A), it was significantly less sensitive to the inhibitory effects of the HDAC inhibitors (Figure 6B). This data suggests that replicative senescence and HDAC inhibitor-induced senescence impacts proteasome activity through a common pathway.
Reduced expression of the β5 proteasome subunit in proliferating WI-38 cells by HDAC inhibitors
HDAC1 is down-regulated in senescent WI-38 cells
The identification of HDACs as a component in replicative senescence, and hence growth arrest, is interesting because data has shown that HDACs can promote tumor growth and stem cell proliferation. For example, it has been reported that HDAC1 overexpression occurs in 68% of primary human gastric cancer, and contributes to colony formation and proliferation of prostate and breast cancer cells [43–45]. Some transformed cell types may exaggerate the expression of HDACs to circumvent replicative senescence. In this regard, cancer cells are similar to stem cells, where HDAC1 is required for full cellular growth potential . This further supports the idea that replicative senescence, and the associated decline in HDAC1 expression, has a tumor suppressing role [4, 47].
It is not entirely clear how HDACs are regulating proteasome subunit expression. In yeast, a common mode of transcriptional regulation of the proteasomal subunits has already been identified [48–50]. Nearly all the yeast subunit homologs have been found to possess proteasome-associated control elements within their promoters. The transcription factor RPN4 has been identified as the component within yeast involved in binding these elements to modulate gene transcription . Remarkably, no homolog of RPN4 has been identified in humans. However, it is still possible that another common transcriptional mechanism is shared amongst the catalytic subunits in human cells. The activity of these putative regulatory proteins may be regulated by acetylation, such that an increased level of acetylation reduces proteasome subunit expression.
Our analysis of HDAC1 and HDAC3 indicates that replicative senescence is not accompanied by a global decline in HDAC expression. Rather, it appears to occur through the down-regulation of HDAC1, and potentially other HDACs. Other groups have also reported a senescence-specific form of the HDAC2 protein . In addition, the NAD+-dependent Sir2 histone deacetylase has been identified to contribute to the replicative life-span in yeast, thus suggesting that the mammalian Sir2-related class III HDACs may contribute to senescence in normal human cell types, as well [51, 52]. It should be noted that it is not clear if the decline in HDAC1 is a cause or a consequence of replicative senescence. However, it seems reasonable to hypothesize that age-related modulations in HDAC levels could be a contributing factor in senescence. Further analysis of individual HDAC proteins may identify their individual functions within the senescence machinery. Anti-aging and anti-cancer strategies may be aimed at increasing or decreasing the activity of specific HDAC proteins.
Our findings indicate that cellular HDAC activity regulates numerous phenotypic changes associated with cellular senescence. Reduced cellular HDAC expression and activity, in association with other events, may be important for mediating the transition to a senescent phenotype.
Cell culture and treatments
The WI-38 human lung fibroblast cell line was purchased from American Type Culture Collection (Manassas, VA). Cells were propagated in minimal essential media containing 2 mM L-glutamine and Earle's salts (E-MEM) supplemented with 10% fetal bovine serum, 0.1 mM non-essential amino acids, 1 mM Sodium Pyruvate, streptomycin (50 mg/ml), and penicillin (50 U/ml). All medium components were purchased from Invitrogen Life Technologies (Carlsbad, CA). WI-38 cells entered senescence at about 50 CPD (Cumulative Population Doublings). Early-passage WI-38 cells (CPD < 30) are referred to as young or pre-senescent cells and displayed high proliferative potential. Late-passage WI-38 cells (CPD > 50) are classified as old or post-senescent cells and exhibited very low proliferative potential. Sodium butyrate (Sigma-Aldrich, St. Louis, MO) was used at the final concentration of 4 mM (unless stated otherwise). TSA (Calbiochem, San Diego, CA) was used at a 2 μM concentration (unless stated otherwise). Cells treated with TSA were given fresh media supplemented with new TSA every 24 hours.
Cytosolic extracts were prepared as described in Inan et al. . For immunoblotting studies, 25 μg of cytoplasmic protein (quantified by the Bio-Rad protein assay) was denatured under reducing conditions, separated on 10% sodium dodecyl sulfate (SDS) polyacrylamide gels, and transferred to nitrocellulose by voltage gradient transfer. The resulting blots were blocked with 5% nonfat dry milk. Specific proteins were detected with appropriate antibodies using enhanced chemiluminescence detection (Santa Cruz Biotechnology, Santa Cruz, CA). Immunoblotting antibodies used were: subunit β1 PW8140, subunit β2 PW8145, subunit β3 PW8130, subunit β4 PW8890, subunit β5 PW8895, subunit β6 PW9000, and subunit β7 PW8135, (Affiniti Research Products Ltd., Mamhead, Exeter, UK); Ubiquitin P1A6, (Santa Cruz Biotechnology, Santa Cruz, CA); p21 C-19, (Santa Cruz Biotechnology, Santa Cruz, CA); and Actin I-19, (Santa Cruz Biotechnology, Santa Cruz, CA). The antibodies specific for ubiquitin and p21WAF1 were diluted 1:500 for immunoblotting. All other antibodies were employed at a 1:1000 dilution. For optical densitometry, immunoblot images were scanned on a UMAX Astra 1220P scanner and analyzed with NIH Image version 1.62. Statistical significance was determined by a paired Student's t-test.
Proteasome activity assay
Proteasome activity was quantified by using a fluorogenic proteasome-specific substrate. The assay is based on the detection of the fluorophore AMC (7-amino-4-methylcoumarin) after cleavage from the synthetic proteasome substrate Suc-LLVY-AMC (Calbiochem, San Diego, CA). Cytosolic extract (5 μg of total protein in 5 μl) was incubated in a 100 μl reaction containing 20 mM Tris-HCL (pH 7.8), 0.5 mM EDTA, 0.035% SDS, and 70 μM Suc-LLVY-AMC for 10 minutes at room temperature. The change in fluorescence (substrate consumption) was measured over an interval of 40 minutes using a microtiter plate fluorometer (excitation, 360 nm; emission, 460 nm). Proteasome-independent activity was determined by performing the assay in the presence of proteasome inhibitor MG-132 (final concentration 60 μM) (Calbiochem, San Diego, CA). Proteasome activity values were derived by subtracting the fluorescence obtained in the presence of this inhibitor from the values obtained in its absence. The values shown represent the ratio in proteasome activity from each sample compared to the activity in young WI-38 cell extracts. Assays were performed in quadruplicate, and statistical significance was determined by a paired Student's t-test.
Senescence-associated β-galactosidase staining
Staining for β-galactosidase activity in WI-38 cells was performed as previously described . WI-38 cells were washed with PBS, fixed in 0.2% glutaraldehyde/2% formaldehyde for 10 minutes at room temperature, and washed again with PBS. Cells were then stained at 37°C (in the absence of CO2) with fresh senescence-associated β-gal (SA-β-gal) staining solution (150 mM NaCl, 2 mM MgCl2, 5 mM potassium ferricyanide, 5 mM potassium ferrocyanide, and 40 mM citric acid/sodium phosphate, pH 6.0) containing 1 mg/ml 5-bromo-4-chloro-3-indolyl-β-D-galactoside (X-gal). Once staining was maximal (12–16 hrs), cells were washed with PBS and overlaid in 70% glycerol. Images were taken at 100 × magnification as viewed by phase contrast.
minimal essential media with Earle's salts
This work was supported in part by an award from the National Cancer Institute to C.G. (R29CA79656)
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