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[Cancer Research 61, 931-934, February 1, 2001]
© 2001 American Association for Cancer Research

Advances in Brief

MS-275, A Histone Deacetylase Inhibitor, Selectively Induces Transforming Growth Factor ß Type II Receptor Expression in Human Breast Cancer Cells

Byoung Ick Lee1, Seok Hee Park1, Jin Woo Kim, Edward A. Sausville, Heung Tae Kim, Osamu Nakanishi, Jane B. Trepel and Seong-Jin Kim2

Laboratory of Cell Regulation and Carcinogenesis [B. I. L., S. H. P., H. T. K., S-J. K.], Developmental Therapeutics Program [E. A. S.], and the Medicine Branch [J. W. K., J. B. T.], National Cancer Institute, Bethesda, Maryland 20892, and Mitsui Pharmaceuticals, Chiba 297-0017, Japan [O. N.]


   ABSTRACT
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Transcriptional repression of the transforming growth factor (TGF)-ß type II receptor (TßRII) gene appears to be a major mechanism to inactivate TGF-ß responsiveness in many human cancers. Because histone acetylation/deacetylation plays a role in transcriptional regulation, we have examined the effect of MS-275, a synthetic inhibitor of histone deacetylase, in human breast cancer cell lines. MS-275 showed antiproliferative activity against all human breast cancer cell lines examined and induced TßRII mRNA, but not TGF-ß type I receptor mRNA. MS-275 caused an accumulation of acetylated histones H3 and H4 in total cellular chromatin. An increase in the accumulation of acetylated histones H3 and H4 was detected in the TßRII promoter after treatment with MS-275. However, the level of histone acetylation did not change in chromatin associated with the TGF-ß type I receptor gene. MS-275 treatment enhanced TGF-ß1-induced plasminogen activator inhibitor 1 expression. Thus, antitumor activity of MS-275 may be mediated in part through the induction of TßRII expression and consequent potentiation of TGF-ß signaling.


   Introduction
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results
 Discussion
 REFERENCES
 
Alterations in chromatin structure by histone modification appear to play a central role in the regulation of gene transcription. Acetylation of core nucleosomal histones is regulated by the opposing activities of histone acetyltransferases and HDACs3 (1, 2, 3) . HDACs catalyze the removal of an acetyl group from the {epsilon}-amino group of lysine side chains of histone H2A, H2B, H3, and H4 and thereby reconstitute the positive charge on lysine. Inhibitors of HDACs have been shown to induce differentiation and/or apoptosis of transformed cells, suggesting that alterations in chromatin structure may also be important in the process of neoplasia (1 , 2) .

HDAC inhibitors such as sodium butyrate, suberoylanilide hydroxamic acid, and trichostatin A appear to arrest human tumor cells at G1 and G2-M phase and induce expression of the cell cycle kinase inhibitor p21WAF1 (4, 5, 6, 7, 8) . Increased expression of p21WAF1 may be one of the critical factors in the growth arrest induced in transformed cells by these agents.

TGF-ß, the prototypic multifunctional cytokine, participates in the regulation of vital cellular activities such as proliferation and differentiation (9 , 10) . Another essential function of TGF-ß is its tumor suppressor activity in a variety of different human cell types. Human cancer cells frequently demonstrate resistance to the normal growth-inhibitory effects of TGF-ß, and it has been proposed that the development of such TGF-ß resistance represents a significant step during carcinogenesis (11, 12, 13) . Many human cancer cell lines including breast and prostate cancer cell lines have TGF-ß resistance without detectable alterations in the TßRII gene (13) . These cells express low or undetectable levels of TßRI and TßRII genes, suggesting that abnormalities of transcriptional regulation, altered mRNA processing, or decreased mRNA stability might be involved.

In this study, we have examined the effect of a synthetic inhibitor of HDAC, MS-275, on the growth of human breast cancer cells and expression of TßRII (14) . We found that MS-275 induces the accumulation of acetylated histones in the chromatin of the TßRII gene and that this increase is associated with an increase in TßRII expression in human breast cancer cell lines. In addition, MS-275 treatment enhanced TGF-ß1-induced PAI-1 expression. These findings indicate that the growth inhibition of human breast cancer cells by MS-275 may be due, at least in part, to the restoration of TGF-ß signaling by inducing TßRII.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Cell Culture.
The human breast cancer cell lines MCF-7, ZR-75, HS-578t, and SKBR3 were cultured in RPMI 1640 without phenol red with 10% charcoal-treated fetal bovine serum and incubated at 37°C with 5% CO2. N-(2-Aminophenyl)-4-[N-(pyridine-3-yl-methoxy-carbonyl)aminomethyl]benzamide (MS-275), an inhibitor of HDAC, was kindly provided by Mitsui Pharmaceuticals (Chiba, Japan; Ref. 14 ).

Northern Blot Analysis.
Total RNA was isolated using Trizol (Life Technologies, Inc., Rockville, MD) according to the manufacturer’s instructions, transferred onto Zeta-Probe blotting membrane (Bio-Rad Laboratories, Hercules, CA), and hybridized with 32P-labeled cDNA for human TßRII, TßRI, PAI-1, or ß-actin.

Acid-soluble Nuclear Protein Preparation and Western Blot Analysis.
Acid-soluble proteins were prepared as described previously (8 , 15) . Cells (5 x 106) were cultured with and without MS-275 (0.5 µM). Protein concentrations of histone preparations were determined using the Bio-Rad Protein Assay Kit with BSA as the standard. Proteins (20 µg protein) were denatured and electrophoresed in 15% polyacrylamide gels for histones. After electrophoresis, samples were transferred onto nitrocellulose. To verify equal protein loading, a parallel protein gel was run and stained with Coomassie Blue. The blots were probed with rabbit antiacetylated histone H3 and rabbit antiacetylated histone H4 (Upstate Biotechnology, Lake Placid, NY) and detected by using the enhanced chemiluminescence method (Pierce).

ChIP Assay.
Cells were plated at a density of 5 x 106 cells/15-cm dish and incubated overnight. The next day, cells were cultured with 0 or 1 µM MS-275 for 24 h. ChIP assay was performed using the method described by Richon et al. (8) . TßRI- and TßRII-specific primers were used to carry out PCR from DNA isolated from ChIP experiments and Input samples. The optimal reaction conditions for PCR were determined for each primer pair. Parameters were denaturation at 95°C for 1 min and annealing at 58°C for 1 min, followed by elongation at 72°C for 1 min. PCR products were analyzed by 2.5% agarose/ethidium bromide gel electrophoresis. The primers of the TßRI promoter (16) for ChIP analysis were 5'-GTGGGGCGTGGCCAGAAAC-3' (-26/-44; uP1) and 5'-GCCCTTTGTAACTGCTCGGAGGAC-3' (+102/+125; dP2). The primers of the TßRII promoter (17) were 5'-CTGGTCTAGGAAACATGATTGG-3' (-77/-98; uP1) and 5'-CGAGTGACTCACTCAACTTCAACTCAG-3' (+54/+33; dP2).


   Results
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
Discussion
 REFERENCES
 
MS-275 Inhibits Proliferation of Human Breast Cancer Cells and Induces Accumulation of Acetylated Histones.
We examined the effect of the HDAC inhibitor MS-275 on the proliferation of human breast cancer cells. Cells were cultured with and without 1 µM MS-275 for 1–5 days. MS-275 inhibited proliferation at 1 µM over the duration of culture (Fig. 1a)Citation . MS-275 at 1 µM inhibited the proliferation of HS-578t cells without loss of cell viability (>95% viable) as determined by trypan blue exclusion, whereas MS-275 at 1 µM caused a 50% loss of cell viability in MCF-7, ZR-75, and SKBR3 cells after 3 days. When the concentration of MS-275 was decreased to a nontoxic dose of 0.5, 0.25, and 0.5 µM in MCF-7, ZR-75, and SKBR3, respectively, no increase in cell density was detected over the duration of culture (Fig. 1, b–d)Citation .



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  		Fig. 1. Antiproliferative effect of MS-275. Cells were incubated with the indicated concentrations of MS-275 for 5 subsequent days in triplicate. Each day, cells were trypsinized and counted. *, P < 0.01. a, HS-578t incubated with 1 µM MS-275; b, MCF-7 incubated with 0.5 µM MS-275; c, ZR-75 incubated with 0.25 µM MS-275; d, SKBR3 incubated with 0.5 µM MS-275.

 
We next examined the level of histone acetylation in MCF-7 and ZR-75 human breast cancer cells after treatment with MS-275. Histones were isolated from cells treated with MS-275 (0.5 µM) for 0, 1, 3, 6, 9, and 24 h. Western blot analysis showed that before incubation with MS-275 (0 h), the levels of acetylated histone H3 and H4 in MCF-7 and ZR-75 breast cancer cells were low, with the exception of the acetylated H3 protein in ZR-75 (Fig. 2, a and b)Citation . The accumulation of acetylated histones H3 and H4 was increased after 6 h, and the maximum levels of acetylated H3 and H4 proteins were detected after 24 h of incubation (Fig. 2, a and b)Citation .



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  		Fig. 2. Western blot analysis of acetylated histone H3 and H4 protein in MCF-7 and ZR-75 human breast cancer cells. Histones were isolated by acid-soluble extraction from MCF-7 (a) and ZR-75 (b) cells cultured for the indicated times with 0. 5 µM MS-275.

 
MS-275 Induces Expression of TßRII mRNA.
To test the hypothesis that TßRII gene expression is suppressed by deacetylation of histones or transcription factors, we treated these breast cancer cell lines with MS-275, an inhibitor of HDACs. As shown in Fig. 3Citation , such treatment resulted in a markedly enhanced expression of the TßRII transcript. However, the TßRI transcript was not induced in cell lines. Receptor cross-linking assays further demonstrated that MS-275 treatment increases the level of TßRII protein (data not shown).



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  		Fig. 3. MS-275 induces TßRII mRNA expression in human breast cancer cell lines. Cells were treated with 1 µM MS-275 for 24 h, and TßRII induction was examined by Northern analysis. Fifteen µg of total RNA were loaded in each lane, with equal loading verified by ethidium bromide staining and ß-actin gene expression.

 
MS-275 Induces Accumulation of Acetylated Histones in Chromatin Associated with the TßRII Gene.
The effect of HDAC inhibition on the acetylation of histone H4 or H3 associated with the TßRII gene promoter was examined using ChIP assay in MCF-7 and ZR-75 human breast cancer cells. Chromatin fragments from cells cultured with and without MS-275 (0.5 µM) for 24 h were immunoprecipitated with an antibody to acetylated histone H3 or H4. DNA from the immunoprecipitate was isolated. As shown in Fig. 4aCitation , a 152-bp fragment of the TßRII promoter region was amplified. After treatment with MS-275, approximately 5.5-fold more TßRII promoter DNA in ZR-75 cells and 8-fold more TßRII promoter DNA in MCF-7 cells using antiacetylated H4 antibodies and 6.5-fold more TßRII promoter DNA in MCF-7 cells using antiacetylated H3 antibodies were associated with highly acetylated histones, compared with the same region isolated from cells cultured without MS-275 (Fig. 4)Citation . The acetylation of histone H4 associated with the TßRII gene was increased in both MCF-7 and ZR-75 cells by treatment with MS-275, whereas the acetylation of histone H3 associated with TßRII was only increased in MCF-7 cells.



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  		Fig. 4. MS-275 induces accumulation of acetylated histone H3 or H4 in chromatin associated with the TßRII gene. a, schematic representation of the promoter and 5' untranslated regions of the human TßRI and TßRII genes. Chromatin fragments from cells cultured with and without MS-275 (0.5 µM) for 24 h were immunoprecipitated with antibody to acetylated histone H3 or H4 in MCF-7 (b) and ZR-75 (c) human breast cancer cells. PCR primers for the region of TßRII and TßRI genes were used to amplify the DNA isolated from the immunoprecipitated chromatin as indicated in "Materials and Methods." b and c were scanned and quantified by a densitometer. The ratio between input DNA and precipitated DNA by H3 and H4 antibody was calculated for each treatment and each primer set. Fold increases were calculated by dividing the signal intensity of the MS-275-treated sample by the signal intensity of the untreated sample.

 
To determine whether this effect is selective for TßRII, we examined the level of histone H4 or H3 acetylation in the TßRI gene. The expression of TßRI gene was not altered by treatment with MS-275 (Figs. 3Citation and 4)Citation . No change in the levels of histone H3 or H4 acetylation was detected after exposure to MS-275 (Fig. 4)Citation . These results suggest that TßRII but not TßRI expression is modulated by the histone deacetylation.

MS-275 Treatment Enhances TGF-ß Signaling.
Because an inhibitor of HDACs has profound effects on cell growth, we could not examine the effect of the enhanced expression of TßRII gene by the treatment of MS-275 on the autocrine and paracrine growth-regulatory activities of TGF-ß in these cells. Therefore, to determine whether reduced expression of TßRII gene by histone deacetylation was responsible for blocking TGF-ß signaling in human breast cancer cells, we examined the expression of the PAI-1 in ZR-75 and HS-578t cells cultured with MS-275 with or without TGF-ß1. MS-275 treatment enhanced expression of PAI-1 mRNA (Fig. 5)Citation . However, treatment with both MS-275 and TGF-ß1 markedly enhanced expression of PAI-1 mRNA (Fig. 5)Citation . These results suggest that treatment with MS-275 enhances TGF-ß1 signaling through the induction of TßRII gene expression.



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  		Fig. 5. MS-275 enhances PAI-1 mRNA expression induced by TGF-ß1. Cells were treated with both MS-275 (1 µM) and TGF-ß1 (5 ng/ml) for 24 h. Total RNA was isolated from these cells and analyzed by Northern blot analysis using 32P-labeled PAI-1 and ß-actin probes.

 

   Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
TGF-ß plays a critical role in many cellular processes by regulating the cell cycle and cell differentiation (9 , 10) . Because the effects of TGF-ß are dependent on the expression of specific cell surface receptors, it has been proposed that the regulation of the expression of these receptors will emerge as an important mechanism for determining cellular responsiveness to TGF-ß. We have recently identified a subset of human gastric cancer cell lines that is resistant to TGF-ß. Further analysis revealed that the cells lack TßRII mRNA expression despite the presence of a normal gene (11) . Transfection of cyclin D1, a gene overexpressed in human malignancies, into human esophageal cells leads to the down-regulation of TßRII expression and TGF-ß resistance (18) . The cause and effect relationship between the loss of TßRII expression and the resistance to TGF-ß has been firmly established by published studies that reported that transfecting breast, colon, liver, and gastric cells with wild-type TßRII successfully restored TGF-ß growth-inhibitory activity (19 , 20) . These observations suggest that the transcriptional repression of TßRII expression may be important in modulating responsiveness to TGF-ß during carcinogenesis.

Gene expression can be suppressed by either a reduced expression of positive transcription factors or an increased expression of transcriptional suppressors. We have shown that the expression of TßRII is regulated by the ets family of transcription factors and that loss of expression of ERT/ESE-1/ESX/jen/Lef-3, a member of the ets transcription factor family, leads to the loss of TßRII expression (21, 22, 23) . In this study, we have shown that MS-275, an inhibitor of HDACs, induces the transcription of TßRII and an accumulation of acetylated histones associated with the promoter of that gene. The accumulation of acetylated histones by MS-275 appears to be specific to TßRII (Fig. 4)Citation . The TßRI gene is not transcriptionally activated, and there is no change in the level of acetylated histone in chromatin associated with this gene in response to MS-275 (Fig. 4)Citation . We have recently shown that TßRI expression is transcriptionally repressed by DNA methylation and that the treatment with a demethylating agent, 5-aza-2'-deoxycytidine, resulted in an increased expression of the TßRI gene, but not the TßRII gene (24) . These results suggest that the expression of TGF-ß receptors is actively inactivated by two distinct epigenetic mechanisms, DNA methylation and histone deacetylation.

HDAC inhibitors such as MS-275, sodium butyrate, and trichostatin induce the expression of p21WAF1 in a p53-independent manner (4, 5, 6, 7, 8) . The promoter region of the p21WAF1 gene responsive to sodium butyrate is required for the activation of the p21WAF1 promoter by TGF-ß (25 , 26) . However, Sp1, but not Sp3, mediates the p21WAF1 promoter activation by TGF-ß, whereas Sp3, but not Sp1, mediates the transcriptional activation of the p21WAF1 promoter by trichostatin A (7) . These findings suggest that HDAC inhibitors may induce the expression of the p21WAF1 gene through both TGF-ß-dependent and -independent mechanisms. The TGF-ß-independent pathway involves Sp3, whereas the TGF-ß-dependent pathway is mediated through the TGF-ß-responsive element in the p21WAF1 promoter by inducing TGF-ß signaling through the induction of TßRII expression.

Several HDAC inhibitors, including oxamflatin (27) , MS-275 (14) , and the hydroxamic acid-based hybrid polar compounds (4 , 5) , inhibit tumor growth in animal models. However, the detailed mechanisms of inhibition of tumor growth are not known. Our present study suggests that the restoration of TGF-ß signaling through the induction of TßRII is a major target of HDAC inhibitors in suppressing tumor growth.


   ACKNOWLEDGMENTS
 
We thank I. Kim and S. P. Patel for helpful discussion and critical review of the manuscript.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 These two authors equally contributed to this work. Back

2 To whom requests for reprints should be addressed, at Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, Bethesda, MD 20892-5055. Phone: (301) 496-8350; Fax: (301) 496-8395; E-mail: kims{at}dce41.nci.nih.gov Back

3 The abbreviations used are: HDAC, histone deacetylase; TGF, transforming growth factor; TßRII, TGF-ß type II receptor; TßRI, TGF-ß type I receptor; PAI, plasminogen activator inhibitor; ChIP, chromatin immunoprecipitation. Back

Received 11/14/00. Accepted 12/ 4/00.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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