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p300 Mediates Androgen-independent Transactivation of the Androgen Receptor by Interleukin 6¹

Departments of Urology [J. D. D., L. J. S., H. H., D. J. T.], Biochemistry, and Molecular Biology [D. J. T.], Mayo Clinic and Foundation, Rochester, Minnesota 55905

	ABSTRACT

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Prostate cancer (PCa) begins as an androgen-dependent tumor that will eventually progress to an androgen-independent stage after androgen ablation. Although little is understood about this transition to androgen independence, the androgen receptor (AR) appears to be involved. The coactivator p300 has been shown to interact with the AR during its androgen-dependent transactivation. We show that p300 is involved downstream of the mitogen-activated protein kinase pathway during transactivation of the AR by interleukin-6 (IL-6). Furthermore, we demonstrate that sequestration of p300 with E1A inhibits the IL-6-dependent transactivation of the AR, and that increasing amounts of p300 reverse this inhibition. A mutant p300 that lacks histone acetyltransferase (HAT) activity did not reverse E1A-mediated inhibition. By using small-interference RNA designed to target p300 transcripts, we demonstrate that, after silencing p300, there was no induction of AR activity by IL-6. These findings reveal a unique role for p300 and its HAT activity, indicating that it is necessary for the ligand-independent transactivation of the AR in androgen-independent PCa cells.

	Introduction

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Initially, most advanced PCa³ is androgen dependent and can be treated effectively with androgen ablation therapy. However, most cases will eventually progress to an androgen-independent stage, at which point there is currently no effective therapy. Thus, progression from androgen dependence to androgen independence is a critical step in PCa development. Recently much attention has been drawn to the AR as a mediator involved in the progression of PCa (1) .

The AR is a member of the steroid nuclear receptor family and is expressed in nearly all PCa tissues, including androgen-refractory tumors and their metastases. The AR directs the assembly and stabilization of the basal transcription apparatus and androgen-dependent cofactors at target gene promoters, thus enhancing transcription (1) .

The coactivator p300 is a functional homologue of the CBP, both of which interact with the AR during its androgen-dependent transactivation (2) . The HAT activity of CBP/p300 is directed toward nucleosomes through interactions with histones. The acetylation of histones weakens their interaction with the DNA, thus facilitating nucleosome displacement and favoring the access of different transcription factors to the DNA template (3) .

One growth factor that has been implicated in androgen-refractory PCa is IL-6. IL-6 is a cytokine that was found initially to be involved in immune and inflammatory responses but now is known to also regulate the growth of many tumor cells. Overexpression of IL-6 has been implicated in the neoplastic transformation of PCa, and IL-6 receptor is expressed in most prostate carcinoma cell lines, including LNCaP (4) . Furthermore, IL-6 has been found to regulate PCa growth and to transactivate AR-dependent gene expression in the absence of androgens (5) . These findings indicate that IL-6 may be involved in the androgen-independent progression of PCa. The pathway by which IL-6 induces AR gene expression remains undefined. Here we show that p300 mediates androgen-independent transactivation of the AR by IL-6 and that the HAT activity of p300 is necessary for this event.

	Materials and Methods

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Cell Culture.
LNCaP cells were purchased from the American Type Culture Collection (Rockville, MD) and maintained in RPMI 1640 (Celox, St. Paul, MN) containing 9% FBS (BioSource International, Rockville, MD).

Transfections and Luciferase Assays.
LNCaP cells (2.8 x 10⁵ in 6-well plates) were plated and, 24 h later, transfected using the Gene Porter Transfection System (Gene Therapy Systems, Inc., San Diego, CA) with plasmids containing full-length p300 (pCI.p300) or its mutant acetyltransferase negative derivative (pCI.p300-HAT), both described previously (6) at quantities described in the figure legends. Plasmid pCMVE1A12S (7) was used at 10 ng/plate. Luciferase reporter (8) containing a PSA promoter (2 32 µg/plate) was used to measure AR transactivation activity in all of the transfections. Twenty-four h posttransfection, cells received fresh medium containing 9% CSS either with or without 50 ng/ml IL-6 (R&D Systems, Minneapolis, MN). Dual Luciferase assays were performed according to the manufacturer’s instructions (Promega, Madison, WI). Transfection efficiency was monitored by cotransfection with plasmid-containing green fluorescent protein (1 µg/plate; Promega) and visualized with a Zeiss fluorescent microscope at 488 nm. Routinely, transfection efficiencies of 45–50% were obtained.

MAPK Inhibition.
LNCaP cells (2.8 x 10⁵) were plated in 6-well plates and transfected as described previously. Twenty-four h posttransfection, medium was changed to RPMI containing 9% CSS and either vehicle alone (ETOH) or 5 µM MAPK inhibitor PD98059 (Sigma, St. Louis, MO). One h later cells received 50 ng/ml IL-6 for 10 min.

Western Blot Analysis.
After transfection, cells were washed once with PBS and lysed in cold radioimmunoprecipitation assay buffer [50 mM Tris-HCl (pH 7.4), 1% NP40, 0.25% sodium deoxycholate, 150 mM NaCl, 1 mM EDTA or EGTA], plus Complete Protease Inhibitor (Roche, Indianapolis, IN). Western blotting was performed using antibodies to Phospho-p42/44 MAPK (Thr202/Tyr204, 9101S;Cell Signaling Technology, Beverly, MA). Immunodetection of ERK-1/2 (C-16; Santa Cruz Biotechnology, Santa Cruz, CA) was used as loading control.

Transfections with siRNA and Immunocytochemistry.
LNCaP cells (1 x 10⁴) were plated on coverslips in 6-well plates in RPMI 1640 containing 9% FBS. After 24 h cells were transfected with 10 µl of 0.2 mM p300 siRNA (5'-AAC CCC UCC UCU UCA GCA CCA-3'; Dharmacon Research, Inc., Lafayette, CO) per well using oligofectamine Reagent (Invitrogen, Carlsbad, CA) according to the manufacturer’s instructions. Forty eight h after transfection, immunocytochemistry was performed using primary antibodies to p300 (C-20) or AR (441; both Santa Cruz Biotechnology), followed by incubation with fluorescent secondary antibodies (Molecular Probes, Eugene, OR). Cells were counterstained with 2 µg/ml bis-benzimide (Sigma, St. Louis, MO) and images visualized with a LSM510 confocal microscope (Carl Zeiss, Inc., Oberkochen, Germany).

Transfections with siRNA and IL-6 Stimulation.
LNCaP cells were plated and transfected as described above. Forty-eight h after transfection, medium was changed to RPMI 1640 with 9% CSS either with or without 50 ng/ml IL-6 for 15 h. Immunocytochemistry was performed, this time using primary antibodies against p300 and PSA (A67-B/E3, Santa Cruz Biotechnology). Fluorescence was quantitated using the KS400 program image analysis program (Carl Zeiss, Inc.).

	Results

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Overexpression of p300 Overcomes the MAPK Pathway Inhibition in IL-6-mediated Transactivation of the AR.
IL-6 has been shown to transactivate the endogenous AR in LNCaP cells. To determine the optimal concentration of IL-6 for AR activation, a dose-response experiment was performed. LNCaP cells were transfected with a Luciferase reporter construct (PSA-LUC) containing an AR-responsive PSA promoter and later treated with increasing amounts of IL-6 resulting in transactivation of the AR in a dose-dependent manner. This effect was mediated in the absence of androgens because we used charcoal-stripped FBS. When cells were treated with the antiandrogen bicalutamide (Casodex) there was no induction of reporter activity by IL-6, which suggested that the increase in activity is attributable to the AR (data not shown). Because the culture medium contains phenol red, it was important to rule out any potential effects of this compound on the experimental results. Therefore, this experiment was repeated with phenol red-free medium. No differences were observed (data not shown).

One proposed mechanism by which IL-6 can activate the AR is through the MAPK pathway (5 , 9) . To determine whether the IL-6 induction of the AR activity involves the MAPK pathway, we used the MAP/ERK kinase (MEK)-1 inhibitor PD98059. Cells transfected with the PSA-LUC reporter were treated with or without PD98059 (Fig. 1A , Lanes 2, 3, and 4) for 1 h. Cells were then treated with 50 ng/ml of IL-6 (Lanes 2, 3, and 4) or vehicle alone (Lane 1). Twelve h later a Dual Luciferase Assay was performed. As shown in Fig. 1A , treatment of cells with PD98059 inhibited the transactivation of the AR by IL-6 (Lane 3), which suggested that the MAPK pathway is involved in the androgen-independent transactivation of AR by IL-6. Previous studies have demonstrated that p300 interacts with the AR and is involved in its androgen-dependent transactivation. Because p300 may be regulated by the MAPK pathway, we decided to assess the role of this cofactor on the IL-6 induced transactivation of the AR by transfecting p300 (1ug) into one group of cells (Lane 4). When cells were transfected with p300, the inhibitory effect of PD98059 was abrogated (Lane 4). To verify the effects of p300 related to the MAPK pathway, phospho-ERK-1/2 and total ERK-1/2 were assayed by Western blot (Fig. 1B) . As expected, phosphorylation of ERK-1 was increased after IL-6 treatment, and this stimulation was abrogated by the MAPK inhibitor. However, phosphorylation of ERK-1 remained low in the presence of IL-6, PD98059, and p300, which suggested that the effects of p300 are downstream of the MAPK pathway. These results suggest that IL-6-mediated transactivation of the AR occurs through the MAPK pathway and likely involves p300 as a target.

View larger version (30K): [in this window] [in a new window] [Download PPT slide]   Fig. 1. IL-6 transactivates the AR through the MAPK pathway, involving p300. In A, LNCaP cells (2.8 x 105 cells/well, in 6-well plate) were transfected with PSA-LUC reporter (2 µg). Twenty-four h later, cells received fresh medium with CSS and were treated with increasing amounts of IL-6 (1 ng/ml, 10 ng/ml, 50 ng/ml) or vehicle alone. Twelve h later, cells were lysed and Dual Luciferase Assay was performed. This figure shows the average of three experiments. In B, LNCaP cells were transfected with PSA-LUC (2 µg) and p300 (1 µg) or empty vector. Twenty-four h after transfection, cells received fresh medium containing CSS. Cells were treated with 5 µM PD98059 or vehicle alone. One h later, cells received IL-6 (50 ng/ml) or vehicle alone. Twelve h later, Dual Luciferase Assay was performed. A second group of cells was transfected as mentioned and treated with PD98059 or vehicle alone. One h later, cells were treated with IL-6 or vehicle alone for 15 min and lysed for Western blot analysis using antibody to phospho-p44/42 MAPK. Total ERK-1/2 was used as loading control. This figure represents the average of three experiments.

Inhibition of p300 and Its HAT Activity Abrogates IL-6-mediated Transactivation of the AR.
Next, we examined the direct role of p300 in the IL-6-mediated transactivation of the AR. We used an expression vector E1A12S, to express E1A, an oncoprotein that sequesters p300, thereby inhibiting its HAT activity (10) . As shown in Fig. 2A , IL-6 enhanced the activity of the reporter 5-fold (Lane 2). In contrast, IL-6-mediated transactivation was repressed by cotransfection with E1A (Lane 3). To assess if the repressing action of E1A was specifically due to an interaction with p300, cells were transfected with increasing amounts of p300 expression vector along with E1A and treated with IL-6. As shown in Lanes 4, 5, and 6 in Fig. 2A , overexpression of p300 reversed the repression of E1A in a dose-dependent manner and, at high doses, even enhanced the transactivation of the AR above that achieved with IL-6 alone.

View larger version (17K): [in this window] [in a new window] [Download PPT slide]   Fig. 2. Inhibition of p300 and its HAT activity abrogates IL-6-mediated transactivation of the AR. In A, LNCaP cells (2.8 x 105 cells/well, in 6-well plate) were transfected with PSA-LUC reporter (2 µg), E1A12S (10 ng), and increasing amounts of p300 (+, 0.25 µg; ++, 0.5 µg; +++, 1 µg). The total amount of transfected DNA was kept constant by using empty vector pcDNA3.1. Twenty-four h after transfection, cell received fresh medium with CSS containing either 50 ng/ml of IL-6, or empty vector. Cells were lysed 12 h later and Luciferase activity was measured. In B, cells were transfected and treated as described above, but using either 1 µg of p300 (Lane 5) or p300-HAT (Lane 4) as shown in the figure. These graphs represent an average of three experiments.

RNA Interference with p300-siRNA Blocks IL-6-dependent Induction of PSA in LNCaP Cells.
To further assess the role of p300 in the IL-6-mediated transactivation of the AR, we used p300 siRNA to knock out the expression of p300. siRNAs are synthetic duplex RNAs (20–25 nucleotides in length) that reconstitute siRNA-protein complexes (siRNPs) and guide specific recognition and targeted cleavage of the mRNA (11) . LNCaP cells were transfected with double-stranded siRNA oligonucleotides specific to p300 (p300-siRNA) and, thus, targeted to disrupt p300 transcripts. Forty-eight h after transfection, cells were immunostained with antibodies to p300 and AR (Fig. 3A) . Cells transfected with p300-siRNA (Fig. 3A , panels 5–7) showed an absence of p300 protein in the cell nuclei (Fig. 3A , panel 7) when compared with control cells (Fig. 3A , panel 3), whereas no change was seen in levels of AR protein or in the appearance of cell nuclei (Fig. 3A , panels 1, 2, 5, and 6). This indicates that the down-regulation of p300 was a result of the decrease in p300 transcripts because of p300-siRNA transfection, and that there was no alteration of AR protein levels or changes in nuclear conformation. As a control, nucleotides containing nonsense sequences were used. In this case there was no alteration of p300 expression as detected by immunocytochemistry (data not shown).

View larger version (40K): [in this window] [in a new window] [Download PPT slide]   Fig. 3. RNA interference of p300 reduces the increased expression of PSA by IL-6. In A, control LNCaP cells (panels 1–4) or LNCaP cells transfected with p300-siRNA (panels 5–8) were immunostained, 48 h after transfection, with antibodies to p300 (panels 3 and 7) or AR (panels 2 and 6). Panels 1 and 2, nuclear staining with bis-benzimide; panels 4 and 8, AR and p300 signal superimposed. In B, control LNCaP cells or cells transfected with p300-siRNA were treated with IL-6 or vehicle alone 48 h after transfection. Sixteen h later, cells were lysed, and Western blotting was performed using PSA antibody. Total ERK-2 antibody was used as loading control.

We next determined the effect of p300 silencing on PSA expression in individual cells by immunostaining. As shown in Fig. 4 , in cells expressing p300 (A2 and B2), PSA expression was enhanced by treatment with IL-6 (B3). After transfection with p300-siRNA (C2 and D2), treatment with IL-6 did not result in an increase in expression of PSA protein (D3). To quantify these results, cells were chosen randomly from three separate experiments, and PSA immunofluorescence was measured. Fig. 4E shows that a generalized block of IL-6-mediated PSA induction was evident after p300 RNA interference. These results confirm that p300 plays a direct role in IL-6 transactivation of the AR.

View larger version (19K): [in this window] [in a new window] [Download PPT slide]   Fig. 4. RNA interference of p300 blocks IL-6-mediated induction of PSA. In A, control LNCaP cells (A and B, panels 1–4) or cells transfected with p300-siRNA (C and D, panels 1–4) were treated with IL-6 (B and D) or vehicle alone (A and C). Sixteen h later, cells were immunostained with antibodies against p300 (red) and PSA (green). A1–D1, nuclear staining with bis-benzimide; A–D, 2–3, p300 and PSA, respectively; A4–D4, the signal for both proteins superimposed. The figure is a representative of three different experiments. In E, cells were randomly chosen from the previous experiments and mean fluorescence intensity of PSA expression was measured in each of them; *, P = 0.039; bar graph, a general average of all of the chosen cells.

	Discussion

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Several studies have suggested that p300, through its HAT activity, alters the positive charge of histones, thus destabilizing the nucleosomes and leaving the DNA-template susceptible to regulation by different transcription factors. Many studies have demonstrated that acetylation plays a major role in transactivation of different receptors (3 , 13) . We showed that a p300 mutant that lacked HAT activity failed to reverse the E1A-inhibition of the AR activity, which indicated that the HAT activity of p300 is necessary to interact with the AR in an IL-6-mediated mechanism.

A very recent publication has shown that the MAPK pathway is required for the activation of the AR by IL-6 (9) . In this study, we confirmed that the inhibition of the MAPK pathway limited IL-6-mediated transactivation of the AR. Furthermore, we showed that p300 could reverse this action, which suggests that IL-6 may directly or indirectly, through the MAPK pathway, induce p300 transcriptional activity. The fact that p300 alone did not induce AR transcriptional activity suggests that other mechanisms dependent on IL-6 are involved. In this regard, it must be taken into account that p300 is a cofactor. Thus, p300 is necessary, but not sufficient, to induce transcription under these conditions.

A recent study suggested that IL-6 increases AR expression (14) . That was not the case in our experiments, because we determined by both Western blot and immunostaining that AR protein levels did not change as a result of treatment with IL-6 or transfection with p300 under these experimental conditions. Furthermore, we found no evidence that the AR was being phosphorylated by p300 during treatment with IL-6. Both positive and negative effects of IL-6 on the proliferation of LNCaP cells have been observed (15) . Under our experimental conditions, IL-6 increased cell growth proliferation 50% after 24 h (data not shown). Thus, these results correlate the positive effect of IL-6 on AR transactivation activity with cell proliferation.

This study does not preclude the possibility that other histone acetylators may also regulate AR transcriptional activity (2) . This could be the case with CBP, which is known to be a histone acetylator. Moreover, CBP has been shown to interact with the AR. Additional possibilities include other nonhistone proteins like p53 (16) , erythroid Kruppel-like factor (17) , and GATA-1 (6) . However, these proteins have not been shown to be regulated by IL-6.

Taken together, our data provide evidence of a mechanism for transactivation of the AR by IL-6 through p300 and its histone acetylation properties. We think that p300 could be a crucial factor in the transactivation of the AR by growth factors in the absence of androgens. These studies may lead to a better understanding of the biology of androgen-independent PCa.

	ACKNOWLEDGMENTS

 
We thank the following for their valuable contributions: James Tarara for assistance with confocal microscopy; Kenneth Peters for the preparation of figures; Drs. Manuel Llano, Martin Fernandez-Zapico, and Charles Young for critical reviews of the manuscript; Dr. Horacio Murillo for helpful discussions; Drs. Robert Kelm (Mayo Clinic/Foundation, Rochester, MN; E1A12S), Charles Young (Mayo Clinic/Foundation, Rochester, MN; PSA-LUC), and Joan Boyes (Institute of Cancer Research, London, United Kingdom; p300 and p300-HAT) for providing plasmids.

	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 Supported by NIH Grants CA91956 and DK60920, the T. J. Martell Foundation, and the Yamanouchi USA Foundation.

² To whom requests for reprints should be addressed, at Departments of Urology, Biochemistry and Molecular Biology, Mayo Foundation, Rochester, MN 55905. Phone: (507) 284-8139; Fax: (507) 284-2384; E-mail: tindall.donald{at}mayo.edu

³ The abbreviations used are: PCa, prostate cancer; IL-6, interleukin 6; AR, androgen receptor; HAT, histone acetyltransferase; PSA, prostate-specific antigen; MAPK, mitogen-activated protein kinase; siRNA, small-interference RNA; CBP, cAMP-response element-binding protein; FBS, fetal bovine serum; CSS, charcoal-stripped serum; ERK, extracellular signal-regulated protein kinase.

Received 5/16/02. Accepted 8/28/02.

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