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Histone Acetylation May Suppress Human Glioma Cell Proliferation When P21waf/Cip1 and Gelsolin Are Induced

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Histone Acetylation May Suppress Human Glioma Cell Proliferation When P21waf/Cip1 and Gelsolin Are Induced Neuro-Oncology Histone acetylation may suppress human glioma cell proliferation when p21WAF/Cip1 and gelsolin are induced Hideki Kamitani, 1 Seijiro Taniura, Kenji Watanabe, Makoto Sakamoto, Takashi Watanabe, and Thomas Eling Department of Neurosurgery, Institute of Neurological Sciences, Faculty of Medicine, Tottori University, Yonago, 683-8504 Japan (H.K., S.T., K.W., M.S., T.W.); Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709 (S.T., T.E.) Histonedeacetylase inhibitors that increasehistone acety- stimulates apoptosis, and that associated molecular lation on transformed cellsare being investigated as mechanismsresponsible for theseeffects include unique anticancer drugs. Theaim of this investigation increasedhistone acetylation as wellas enhanced expres- was to evaluate an antiproliferative activity of the histone sion of p21 and gelsolin. Neuro-Oncology 4, 95–101, deacetylase inhibitors sodium butyrate (NaBT)and tri- 2002 (Posted to Neuro-Oncology [serial online], Doc. chostatin Aon 5glioma celllines, T98G, A172, U-87 MG, 01-056, March 1, 2002. URL <neuro-oncology.mc. U-118 MG,and U-373 MG,with the examination of the duke.edu>) altered expressions in p21 and gelsolin genes. Treatment with 5-mMNaBT and 40 ng/mltrichostatin Afor 48 h ftersurgical resectionof glioblastomas and anaplas- caused morethan a50% growth inhibition in 5cell ticgliomas, chemotherapy in combination with lines as measuredby cell proliferation assays. An radiotherapy iscurrently one of the primeadjuvant increasein histone acetylation wascon rmed in each cell A treatments(Brandes etal., 2000). Nitrosourea and plat- line. Aftertreatment with 5mMNaBT ,T98G, A172, inum drugs are widely administered to glioma patients and U118 cellsundergo apoptosis as indicated by DNA (Frenay etal., 2000; Shapiro etal., 1989; Takakura etal., ladder formation. Treatmentwith NaBTand trichostatin 1986), but are not particularly effectiveas indicated by the Aalso decreasedDNA synthesis as examined by the u- lack of progress that has been made in improving theef - orescence-activatedcellsorting analysis in T98G and cacy of chemotherapy for malignant gliomas during the U87 cells.In addition to the suppression of cellgrowth, past 25 years (Brandes etal., 2000). Newmodalities of the up regulation of p21 and gelsolin expression was anticancer drugs are thus required to advance treatmentof observed after treatmentwith NaBT,especially in T98G malignant gliomas. cells.Maximum expression of p21 and gelsolin was HDAC2 inhibitors that induce acetylation of nuclear observed within 24 hafter treatment.Results from our in histones play a crucial role in gene expression (Csordas, vitro studies indicate that the treatmentof human glioma 1990) and are novel antiproliferative agents that could be cellswith one of the histone deacetylase inhibitors sup- developed into drugs to treat cancer. The HDAC pressescell growth with decreasing DNAsynthesis and inhibitor NaBT has been shown to induce cell cycle arrest or differentiation in various tumor cells (Riggs et al., 1977). Another HDAC inhibitor, TSA, strongly induces Received 9 October 2001, accepted 9 January 2002. cell differentiation in erythroleukemia cells (Yoshida et 1Address correspondence and reprint requests to Hideki Kamitani, al., 1987). The molecular target for both agents is the 36-1, Nishi-cho, Yonago, Tottori 683-8504 Japan. enzyme histone deacetylase, which regulates histone 2Abbreviations used are as follows: FBS, fetal bovine serum; HDAC, acetylation. These agents inhibit the deacetylase and are histone deacetylase; NaBT, sodium butyrate; SDS-PAGE, sodium thus classified as HDAC inhibitors (Ausio and van dodecyl sulfate–polyacrylamide gel electrophoresis; TSA, trichostatin A. Holde, 1986). As a result of this activity, HDAC Neuro-Oncology APRIL 2002 95 H. Kamitani et al.: Histone acetylation in glioma inhibitors modify the transcriptional regulation for sev- DNA Fragmentation Assay eral genes, including g-globin (MaCaffrey et al., 1997), p21 (Archer et al., 1998), gelsolin (Saito et al., 1999), After treatment with HDAC inhibitors, the oating cells c-MYB (Thompson et al., 1998), and 15-lipoxygenase were collected and sedimented. Cell pellets were washed, (Kamitani et al., 1998). Because the growth-inhibitory resuspended in cell lysis buffer (10-mM Tris-HCl effect and the modification of gene activation occur [pH 7.4], 10-mM EDTA [pH 8.0], 0.5% Triton X-100], simultaneously by treatment with HDAC inhibitors, and incubated. RNase A (0.5 mg/ml) and proteinase K these agents have attracted considerable interest among (0.5 mg/ml) were added, and the pellets were incubated oncologists as promising anticancer drugs. for 2h. DNA was precipitated by ethanol and resus- 6 The interestin HDACinhibitors as anticancer drugs pended in distilled water; 1 ´ 10 cells were electro- evoked the discovery and development of newdrugs, phoresed on a 1.5% agarose gel. The gel was stained with such as trapoxin (Kijima etal., 1993), depudecin (Kwon ethidium bromide, and the DNA was visualized using a etal., 1998), FR901228 (Nakajima etal., 1998), oxam- UV transilluminater. atin (Kimet al., 1999), MS-27-275 (Saito etal., 1999), suberoylanilide hydroxamic acid (Butler etal., 2000), Cell Cycle Analysis by Flow Cytometry and apicidin (Han etal., 2000). Thesedrugs and the clas- sical HDACinhibitors wereevaluated for anticancer Cellswere harvested by trypsinization, and the cellsuspen- activity toward various tumorsin vitro and in vivo, but sion was washed twicein phosphate-buffered saline, then little information is known about the effectof HDAC xed in 70% ice-coldethanol, and storedat 4 °C. Before inhibitors on gliomas. analysis, xed cellswere treated with RNaseA(0.5 mg/ml) Herewe have studied mainly the effectof NaBT,arep- and stained with propidium iodide (50 mg/ml).Cell cycle resentative HDACinhibitor ,on 5glioma celllines. Our analysis was performedwith FACSort equipped with Cell- analysis included measurementof cellgrowth, cellcycle Questsoftware (Becton Dickinson, San Jose,Calif.) by gat- analysis, and apoptotic response. Furthermore, the ing on an area-versus-width dot plot to exclude cell expression of p21 (Waldman etal., 1995) and gelsolin doublets and other clumps. Cells(7500) wereexamined (Sakai etal., 1999), which function as cellcycle regula- and sub-G1 values wereobtained using standard histogram tors, wereexamined in glioma celllines after treatment analysis. Cellcycle analysis was done by aModFit LTver- with HDACinhibitors. sion 2.0 (Verity Software House, Inc., Topsham, Me.). Histone Isolation and Fractionation Materials and Methods The cell pellets were washed twice with 0.5 ml lysis Cell Culture buffer (10 mM Tris [pH 8.0] and 13 mM EDTA) and resuspended in cold distilled water; sulfuric acid was The human malignant glioma cell lines, T98G, A172, added to 0.4-N final concentration. The lysates were U-118 MG, U-373 MG, and U-87 MG, were obtained incubated on ice for 1h and centrifuged (10,000 g, from the American Type Culture Collection (ATCC; 5min). Total histones were precipitated from the super- Manassas, Va. ). The cells were grown in Eagle’s minimal natants with 10 ´ volumes of acetone at –20 °C over- essential medium, 10% FBS (Summit, Fort Collins, night. The precipitated histones were collected by Colo.) with 1-mM sodium pyruvate (Life Technologies, centrifugation, dried, and resuspended in distilled water. Inc., Paisley, U.K.) The media for cells contained gentam- Histone acetylation was evaluated by fractionating his- icin (1 mg/100 ml, Life Technologies, Inc.). The com- tones on acid/urea/polyacrylamide gels. The lower gel pounds of HDAC inhibitors NaBT and TSA were was 15% acrylamide, 2.5 M urea, 5% acetic acid with obtained from Sigma (St. Louis, Mo.). The NaBT and 0.5% N,N,N’,N’-tetramethylethylenediamine, and TSA were solubilized by phosphate-buffered saline and 0.12% ammonium persulfate. The stacking gel was dimethylsulfoxide, respectively. 7.5% acrylamide, 2.5 M urea, 5% acetic acid, 0.75% N,N,N’,N’-tetramethylethylenediamine, and 0.15% Cell Proliferation Assay ammonium persulfate. After samples were loaded, the gel was run for 12 h at 80 vol. Both histone and histone The cell growth and cytotoxicity were assessed by the cell H4 derived from calf thymus were purchased from proliferation assay solution, which is commercially avail- Boehringer-Mannheim (Indianapolis, Ind.) and were able as CellTiter 96 AQueous One Solution (Promega, loaded as standards for unacetylated histone protein. Madison, Wis.) . In a 96-well plate, each well was seeded Gels were xed and stained for 1h in 0.25% Coomassie with 5000 cells in 100 µl media and was allowed to incu- blue/10% aceticacid/ 40% methanol by volume, then bate for 24 h at 37 °C before replacing the FBS media destained with repeated changes of acetic acid/methanol. with media containing the HDAC inhibitors. CellTiter solution (20 µl) was added to each well, the plate was SDS-PAGE and Immunoblot Analysis incubated for 1h at 37 °C, and the absorbance was recorded at 490 nm using a 96-well plate reader. The The antibodies for immunoblot analysis wereobtained ratio of the absorbance value of each HDAC inhibitor fromSanta CruzBiotechnology (Santa Cruz,Calif.). The treatment versus FBS-conditioned cells was plotted on the polyclonal goat anti- p21 antibody,the polyclonal goat proliferation curve. antigelsolin antibody,and the polyclonal goat anti-actin 96 Neuro-Oncology AP RIL 200 2 H. Kamitani et al.: Histone
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