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J. Biol. Chem., Vol. 278, Issue 37, 35775-35780, September 12, 2003
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¶
From the
Department of Pharmacology and
Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263 and the
Department of Medicine, The University of Texas
Health Science Center, San Antonio, Texas 78229
Received for publication, June 5, 2003
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONEXPERIMENTAL PROCEDURESRESULTS AND DISCUSSIONREFERENCES |
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receptors in
MCF-7L breast cancer cells. We now report that histone deacetylase inhibitor
trichostatin A (TSA) induces acetylation of Sp3, which acts as a
transcriptional activator of transforming growth factor- receptor type
II (RII) in MCF-7L cells. Mutation analysis indicated the TSA response is
mediated through a GC box located on the RII promoter, which was previously
identified as an Sp1/Sp3-binding site that was critical for RII promoter
activity. Ectopic Sp3 expression in Sp3-deficient MCF-7E breast cancer cells
repressed RII promoter activity in the absence of TSA. However, in the
TSA-treated MCF-7E cells ectopic Sp3 activated RII promoter. Histone
acetyltransferase p300 was shown to acetylate Sp3. Sp3-mediated RII promoter
activity was stimulated by wild type p300 but not the histone
acetyltransferase domain-deleted mutant p300 in MCF-7L cells, suggesting the
positive effect of p300 acetylase activity on Sp3. Consequently, the results
presented in this manuscript demonstrate that acetylation acts as a switch
that controls the repressor and activator role of Sp3. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTS AND DISCUSSIONREFERENCES |
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(TGF-)1 receptor
type II promoter as a target in these studies and demonstrated that
acetylation stimulates but does not silence Sp3 activity.
TGF- plays a significant role in the growth inhibition of most normal
epithelial and some cancer cells. TGF- mediates its biological affects
through cell surface receptors known as type I (RI) and type II (RII)
(6). Because RI and RII are
required for TGF--mediated growth inhibition, loss of either receptor
contributes to TGF- resistance, loss of TGF- tumor suppressor
activity, and subsequent tumor formation and progression
(7–9).
TGF- resistance due to methylation of the RI promoter or RI promoter
repression by Sp1 deficiency was reported in gastric and colon cancer cells
(10,
11). Mutational inactivation
of the RII gene in genetic syndromes of gastric and colon carcinoma has
identified the RII gene as a tumor suppressor
(8,
12,
13). Transcriptional
repression of RII due to reduced binding of nuclear proteins to the RII
promoter in keratinocytes, pancreatic cancer cells, and breast cancer cells
has been shown as a cause for TGF- resistance
(14–16).
Ectopic RI and RII expression in RI- and RII-deficient cells led to
restoration of TGF- response and reversal of malignancy in breast and
colon cancer cells (7,
9). Thus, the loss of
transcriptional control of RII expression appears to have a significant role
in determining the malignant phenotype of a broad variety of types of cancer
cells.
The RII promoter has been characterized
(17). The RII promoter lacks a
distinct TATA box, is GC-rich, and depends upon the Sp1 transcription factor
for the initiation of transcription. The RII promoter contains two consensus
Sp1 sites (–25 bp and –143 bp relative to the transcription start
site). MCF-7L breast cancer and MIA PaCa-2 pancreatic cancer cells are
resistant to growth inhibition by TGF- because of reduced transcription
of RII. This was partly due to reduced/low levels of Sp1 expression in these
cells (15,
16). Subsequently, we showed
that unmodified Sp3 acts as a transcriptional repressor of RII in MCF-7L cells
(18) and DNA methyltransferase
inhibitor, 5 azacytidine induces RII expression in cancer cells through a
combination of increased Sp1 and decreased Sp3 protein levels/activities
(19). We now report that
treatment of MCF-7L breast cancer cells with the histone deacetylase inhibitor
trichostatin A (TSA) induces acetylation of Sp3 in addition to accumulation of
acetylated histones H3 and H4 in association with RII promoter DNA.
Acetylation of transcription factors such as p53, E2F1, Myo D, and EKLF has
been shown to enhance transcriptional potency and affect protein-protein
interactions (4). TSA response
is mediated through a GC box on the RII promoter, which was previously
identified as an Sp1/Sp3-binding site that was critical for RII promoter
activity in MCF-7L cells (15,
18). TSA did not affect RII
expression by altering Sp1/Sp3 binding affinities. This was interesting
because unmodified Sp3 acts as a repressor of RII in MCF-7L cells
(18). So, we hypothesized that
acetylated Sp3 acts as an activator of RII in TSA-treated MCF-7L cells.
Ectopic Sp3 expression in Sp3-deficient RII-positive MCF-7E cells repressed
RII promoter activity in the absence of TSA. However, in the TSA-treated
MCF-7E cells ectopic Sp3 stimulated RII promoter activity. Sp3 undergoes
acetylation by p300 (4). We
observed that wild type p300 but not the histone acetyltransferase (HAT)
domain deleted mutant p300 up-regulated Sp3-mediated RII promoter activity in
MCF-7L cells, suggesting the positive influence of p300 acetylase activity on
Sp3 transcriptional activity. Consequently, the results presented in this
report demonstrate that acetylation status of Sp3 determines the activator or
repressor function of Sp3.
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EXPERIMENTAL PROCEDURES |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTS AND DISCUSSIONREFERENCES |
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Chromatin Immunoprecipitation (ChIP) Assay—MCF-7L and MIA
PaCa-2 cells were plated at a density of 4 x 106 cells/15-cm
dish and incubated overnight at 37 °C with 5% CO2. The next
day, cells were cultured with 0 or 100 ng/ml TSA for 24 h. The ChIP assay was
performed as described previously
(20). RII and actin 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 annealed
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 following primers were used for PCR: RII promoter, sense, GAG AGA GCT AGG
GGC TGG; antisense, CTC AAC TTC AAC TCA GCG CTGC; -actin, sense, CCA ACG
CCA AAA CTC CC; antisense, AGC CAT AAA AGG CAA CTT TCG.
Immunoprecipitation and Western Blot Analysis—Nuclear extracts were obtained from control and TSA-treated MCF-7L breast cancer cells. Equal amounts of nuclear extracts were immunoprecipitated with rabbit anti-human Sp3 polyclonal antibody (Upstate Biotechnology). Immunocomplexes were resolved by 7.5% SDS-PAGE and then blotted with pan-acetyl lysine or goat anti-human Sp3 antibodies (Santa Cruz Biotechnology).
Transfections and Luciferase Assay—The RII (–219 bp
RII-Luc) promoter-luciferase reporter construct was used to determine RII
promoter activity (21). The
RII-Luc construct and control null vector without RII promoter insert (pGL2)
were transiently transfected into MCF-7L breast cancer cells using the FuGENE
6 method (Roche Applied Science) with a -galactosidase plasmid for
normalization (18). Cells were
treated with 100 ng/ml of TSA 4 h following transfection. Cells were harvested
at 24 h following TSA treatment, and promoter activities were determined using
a commercial luciferase assay (Luciferase Assay System, Promega). To analyze
the ectopic Sp3 effects in the presence and absence of TSA, Sp3-deficient
MCF-7E cells were transfected with RII promoter-luciferase reporter or PGL2
control vector without RII promoter and CMV-Sp3 cDNA along with
-galactosidase plasmid for normalization. Cells were treated with TSA 4
h following transfection. Cells were harvested at 24 h following TSA
treatment, and promoter activities were determined. To determine the effects
of histone acetyltransferase p300 on Sp3-mediated RII promoter activity, wild
type p300 (CMV-p300) or HAT domain-deleted mutant p300 (CMV-p300
HAT)
along with RII-Luc plasmid were transfected into MCF-7L cells. Cells were
harvested 48 h following transfection, and luciferase activity was determined
following normalization to -galactosidase.
Transfections and Chloramphenicol Acetyltransferase (CAT)
Assay— The –47 bp RII-CAT (wild type GC box, Sp1 site) and
–47 bp Spm RII-CAT (mutated GC box, Sp1 site) constructs were described
previously (15). The above
constructs were transiently transfected into MCF-7L cells using the FuGENE 6
method (Roche Applied Science). For normalization of transfection efficiency,
-galactosidase plasmid was co-transfected into the cells. Cells were
treated with 100 ng/ml of TSA 4 h following transfection. At 24 h following
TSA treatment, cells were harvested to carry out the standard
-galactosidase and CAT assays
(15). Results from CAT assays
were analyzed by thin layer chromatography (TLC), and the TLC plate was
quantitated directly using an alpha imager system.
Histone Deacetylase Assay—We immunoprecipitated endogenous Sp1/Sp3 from 500 µg of MCF-7L nuclear extracts using agarose-conjugated anti-rabbit Sp1/Sp3 polyclonal or control IgG antibodies. The beads were washed four times with 1 ml of phosphate-buffered saline and assayed for deacetylase activity using the HDAC fluorescent activity assay/drug discovery kit (AK-500; BIOMOL Research Laboratories). Briefly, beads were incubated with 100 µM acetylated substrate in 100 µl assay buffer containing or lacking 1 µM TSA. Incubation of the reaction at 37 °C for 30 min allowed deacetylation of the substrate, which sensitized it to treatment with the developer and produced a fluorophore detectable on a fluorometric reader (excitation at 360 nm and emission at 450 nm).
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RESULTS AND DISCUSSION |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTS AND DISCUSSIONREFERENCES |
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receptors RI and RII are essential for
TGF--mediated growth suppression of normal epithelial and some cancer
cells. TGF- resistance due to loss of expression of RI or RII has been
linked to tumor formation and progression
(7–9).
Ectopic RII expression in receptor-deficient cancer cells reduced
tumorigenicity in athymic nude mice, thus indicating the role of RII as a
tumor suppressor (7,
8). MCF-7L breast and MIA
PaCa-2 pancreatic cancer cells acquire resistance to growth inhibition by
TGF- due to reduced transcription of RII
(15,
16). Recent studies
(16,
19,
20,
23,
24) indicated DNA methylation
and histone deacetylation as modes of inactivation of several genes. ChIP
analysis was used to examine the effect of HDAC inhibition on the acetylation
of histones H3 or H4 associated with the RII gene promoter. Chromatin
fragments from cells cultured with or without TSA for 24 h were
immunoprecipitated with antibodies to acetylated histones H3 or H4. DNA from
the immunoprecipitate was isolated, and PCR using RII promoter primers was
performed (Fig. 1).
Accumulation of RII with highly acetylated histones H3 and H4 was observed in
TSA-treated MCF-7L and MIA PaCa-2 cells in comparison to untreated control
cells. The accumulation of acetylated histones H3 and H4 indicated histone
deacetylation was involved in the transcriptional repression of RII. The TSA
effect on RII is selective because the -actin gene was not affected. The
transcription of RII promoter may be repressed by a compact chromatin
structure, which is maintained by increased HDAC activity in MCF-7L cells.
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TSA Effects Are Mediated by a GC Box on the RII Promoter— TSA-treated MCF-7L cells showed enhanced RII mRNA expression (data not shown). To determine whether the enhanced RII expression levels following TSA treatment were due to increased RII transcription we analyzed RII promoter activities using an RII promoter-luciferase reporter construct in control and TSA-treated MCF-7L cells. The RII promoter exhibited enhanced activity in the presence of TSA (Fig. 2). The RII promoter lacks a distinct TATA box and is highly GC-rich. It contains two GC boxes at –25 bp and –143 bp relative to the transcription start site, which have been characterized as Sp1-binding sites (17). We have shown previously that the GC box at –25 bp is critical for RII promoter activity in MCF-7L cells (15). This site also mediates the transcriptional repression of RII by Sp3 (22). To determine whether the TSA effects are mediated through this GC box on the RII promoter, we analyzed the activities of wild type (–47 bp RII-CAT) and mutant GC box (–47 bp Spm RII-CAT) RII promoter constructs in control and TSA-treated MCF-7L cells. Although the activity of the wild type GC box RII promoter was up-regulated in the presence of TSA, the mutant GC box RII construct was not modulated, thus confirming that TSA effects are mediated through this GC box (Fig. 3).
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Effect of TSA on Sp1 and Sp3 Binding Affinities and Their Association with HDAC1 and p300 —We previously reported (15, 16) that MCF-7L and MIA PaCa-2 cells express reduced levels of Sp1 protein. In addition MCF-7L cells express high levels of Sp3 protein, which acts as a transcriptional repressor of RII (18). Inhibition of DNA methylation by 5 azacytidine induced RII expression through a combination of increased Sp1 and decreased Sp3 binding affinities (19). To determine whether the TSA-mediated RII expression is through modulation of Sp1 and Sp3 binding affinities, we carried out electrophoretic mobility shift assays on control and TSA-treated MCF-7L nuclear extracts using 32P-labeled consensus Sp1 oligonucleotide. Both the control and TSA-treated MCF-7L nuclear extracts showed the high Sp3 binding and low Sp1 binding pattern we had previously observed in these cells (18). This indicated TSA treatment did not enhance transcription through modulation of Sp1 and Sp3 binding affinities (data not shown). ChIP analysis using Sp1/Sp3 antibodies also did not show any change in the Sp1/Sp3-associated RII promoter DNA in TSA-treated MCF-7L cells (data not shown). Consequently, TSA mediates RII promoter activities by a mechanism other than alteration of the DNA binding activities of Sp1 and Sp3. This data is consistent with several other reports indicating histone deacetylase inhibitors induce the expression of target genes without altering the Sp1/Sp3 binding affinities (23–25). The mechanism of RII induction by TSA may involve modifications of Sp1 and/or Sp3 proteins, alterations in their interaction with other proteins, or modulation of proteins directly or indirectly interacting with Sp1 and/or Sp3. Co-immunoprecipitation experiments using Sp1/Sp3 and HDAC1/p300 antibodies indicated that Sp1 as well as Sp3 interacts with HDAC1 and p300. However, these interactions were not affected by TSA, thus ruling out alterations in the association of Sp1/Sp3 and HDAC1/p300 as a cause for RII induction in MCF-7L cells. The transcription of RII promoter may be repressed by a compact chromatin structure, which is maintained by increased HDAC activity in MCF-7L cells. Thus, we hypothesized that TSA was acting by inhibiting HDAC enzymatic activity associated with Sp1 and Sp3.
Sp1/Sp3 Associates with Histone Deacetylase Activity—To test whether Sp1/Sp3 associates with an active histone deacetylase, we immunoprecipitated endogenous Sp1/Sp3 from MCF-7L nuclear extracts using anti-Sp1 and anti-Sp3 or control IgG antibodies. The precipitated complexes were tested for their ability to deacetylate an acetylated histone substrate (Fig. 4). We showed that Sp1 as well as Sp3 associate with deacetylase activity, and this activity is abolished when the deacetylase inhibitor TSA is included in the deacetylation reaction, suggesting that the histone deacetylase activity associated with Sp1 and Sp3 is completely sensitive to TSA. TSA treatment suppresses the Sp1/Sp3-associated HDAC activity leading to a local disruption of the nucleosome structure of the RII promoter by acetylation of histones H3 and H4. It is interesting to note that TSA induced RII expression in MCF-7L cells without decreasing Sp3 binding, because we have previously reported that Sp3 acts as a transcriptional repressor of RII in these cells (18). One plausible reason may be that unmodified Sp3 acts as a transcriptional repressor, and TSA-mediated Sp3 modification may convert Sp3 into transcriptional activator.
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Sp3 Acetylation and RII Promoter Activity—The lysine residue
in the inhibitory domain of Sp3 was shown to be susceptible to acetylation,
and it was hypothesized that acetylation silences Sp3 activity
(4). However, it was later
reported that sumo modification of the same lysine residue of Sp3 silences Sp3
activity (5). Consequently, the
functional role of Sp3 acetylation was unclear. We previously reported that
unmodified Sp3 acts as a transcriptional repressor of RII in MCF-7L cells
(18). To determine whether
TSA-mediated Sp3 acetylation is involved in the transcriptional activation of
RII, we analyzed the acetylation status of Sp3 using a pan-acetyl lysine
antibody in control and TSA-treated MCF-7L cells. TSA induced acetylation of
Sp3 in MCF-7L cells (Fig. 5).
Sp3 expression levels were used to normalize protein. Acetylation of
transcription factors such as p53, E2F1, Myo D, and EKLF has been shown to
enhance transcriptional potency and affect protein-protein interactions
(4). We have previously shown
(18) that RII-positive MCF-7E
breast cancer cells express Sp1 protein but were Sp3-deficient. To confirm
that the TSA-mediated Sp3 modification affects RII promoter activity, we have
analyzed effects of ectopic expression of Sp3 on the RII promoter activity in
control and TSA-treated, Sp3-deficient MCF-7E breast cancer cells. Although
ectopic Sp3 repressed RII promoter in the absence of TSA, Sp3 stimulated RII
promoter activity in the TSA-treated cells
(Fig. 6). Histone
acetyltransferase p300 has been reported to acetylate Sp3 protein
(4). Because MCF-7L cells
express high levels of Sp3 and the protein was shown to repress RII promoter
activity, we wanted to ascertain if histone acetyltransferase p300 was able to
stimulate Sp3 transactivation of the RII promoter. We co-transfected wild type
CMV-p300 or HAT domain deleted mutant p300 vector (CMV-p300HAT) along
with the RII promoter-luciferase construct in MCF-7L cells and analyzed the
RII promoter activities (Fig.
7). The wild type p300 stimulated Sp3-mediated RII promoter
activity but not the acetyltransferase activity null p300 mutant. This result
suggests that p300 acts as a co-activator of Sp3 and/or possibly the acetylase
activity of p300 is involved in the acetylation of Sp3 and the concomitant
activation of RII promoter. Histone acetyltransferase p300 but not PCAF has
been shown to acetylate Sp3 protein
(4). PCAF has been shown to
associate with NF-Y in the transcriptional activation of RII
(27). It was also shown that
binding to the GC box by Sp1/Sp3 was influenced by the presence of an intact
NF-Y-binding site on the RII promoter
(22). Consequently, it is
plausible that p300-mediated Sp3 acetylation as well as PCAF and NF-Y
association contributes to RII expression in TSA-treated MCF-7L cells. This is
the first report indicating that acetylation turns Sp3 from a transcriptional
repressor to transcriptional activator.
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FOOTNOTES |
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¶ To whom correspondence should be addressed: Dept. of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Elm and Carlton Sts., Buffalo, NY 14263. Tel.: 716-845-3557; Fax: 716-845-4437; E-mail: michael.brattain{at}roswellpark.org.
1 The abbreviations used are: TGF-, transforming growth factor; TSA,
trichostatin A; RII, receptor type II; HAT, histone acetyltransferase; ChIP,
chromatin immunoprecipitation; Luc, luciferase; CAT, chloramphenicol
acetyltransferase; TLC, thin layer chromatography; HDAC, histone
deacetylase.
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ACKNOWLEDGMENTS |
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REFERENCES |
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TOPABSTRACTINTRODUCTIONEXPERIMENTAL PROCEDURESRESULTS AND DISCUSSIONREFERENCES |
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