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Histone Acetyltransferase PCAF Is Required for Hedgehog– Gli-Dependent Transcription and Cancer Cell Proliferation

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Histone Acetyltransferase PCAF Is Required for Hedgehog– Gli-Dependent Transcription and Cancer Cell Proliferation Published OnlineFirst August 13, 2013; DOI: 10.1158/0008-5472.CAN-12-4660 Cancer Tumor and Stem Cell Biology Research Histone Acetyltransferase PCAF Is Required for Hedgehog– Gli-Dependent Transcription and Cancer Cell Proliferation Martina Malatesta1,2, Cornelia Steinhauer1,2, Faizaan Mohammad1,2, Deo P. Pandey1,2, Massimo Squatrito4, and Kristian Helin1,2,3 Abstract The Hedgehog (Hh) signaling pathway plays an important role in embryonic patterning and development of many tissues and organs as well as in maintaining and repairing mature tissues in adults. Uncontrolled activation of the Hh–Gli pathway has been implicated in developmental abnormalities as well as in several cancers, including brain tumors like medulloblastoma and glioblastoma. Inhibition of aberrant Hh–Gli signaling has, thus, emerged as an attractive approach for anticancer therapy; however, the mechanisms that mediate Hh–Gli signaling in vertebrates remain poorly understood. Here, we show that the histone acetyltransferase PCAF/KAT2B is an important factor of the Hh pathway. Specifically, we show that PCAF depletion impairs Hh activity and reduces expression of Hh target genes. Consequently, PCAF downregulation in medulloblastoma and glioblastoma cells leads to decreased proliferation and increased apoptosis. In addition, we found that PCAF interacts with GLI1, the downstream effector in the Hh–Gli pathway, and that PCAF or GLI1 loss reduces the levels of H3K9 acetylation on Hh target gene promoters. Finally, we observed that PCAF silencing reduces the tumor-forming potential of neural stem cells in vivo. In summary, our study identified the acetyltransferase PCAF as a positive cofactor of the Hh–Gli signaling pathway, leading us to propose PCAF as a candidate therapeutic target for the treatment of patients with medulloblastoma and glioblastoma. Cancer Res; 73(20); 1–11. Ó2013 AACR. Introduction by Hh signaling, suggesting a regulation of the pathway The evolutionary conserved Hedgehog (Hh) signaling path- through both a positive and a negative feedback (8). way plays an important role in development, proliferation, and The importance of the Hh pathway in tumorigenesis was fi stem cell maintenance (1, 2). In agreement with such role, rst discovered in patients of Gorlin syndrome. This rare PTCH deregulation of the Hh pathway leads to several developmental pathology is caused by an inactivating mutation in , syndromes and tumors of different tissues (3, 4). In mammals, which leads to the development of tumors like basal cell Hh signaling is initiated when the secreted Hh proteins bind to carcinoma, medulloblastoma, and rhabdomyosarcoma (9). In and inhibit the transmembrane receptor PTCH. The interac- addition, inappropriate activation of Hh signaling has been tion between Hh and PTCH releases Smoothened (SMO), a shown to lead to the development of tumors in the lung, – second transmembrane protein, which in turn induces the gastrointestinal tract, and pancreas (10 12). GLI1 fi downstream components of the Hh signaling pathway and was originally isolated as a highly ampli ed gene in fi leads to the activation of the glioma-associated oncogene (GLI) human malignant glioma and subsequently found ampli ed transcription factor family (5). When activated, the GLI pro- in other tumor types, including liposarcoma, rhabdomyo- GLI1 teins induce the expression of genes that regulate multiple sarcoma, and osteosarcoma (9, 13, 14). is a key regu- cellular functions such as cell-cycle progression, proliferation, lator of glioma growth and of cancer stem cell self-renewal. and apoptosis (6, 7). In addition, GLI1 and PTCH are activated Moreover studies in transgenic mice have shown that ectop- ic expression of Gli1 is sufficienttoinducebasalcellcar- cinoma (15–17). Despite the importance of the Hh pathway in development and disease, the molecular mechanisms by which the Hh signal Authors' Affiliations: 1Biotech Research and Innovation Centre (BRIC) and 2Centre for Epigenetics, University of Copenhagen; 3The Danish Stem leads to the activation of GLI-regulated transcription is still not Cell Center (Danstem), Copenhagen, Denmark; and 4F-BBVA Cancer Cell completely understood. Here, we show that transcriptional Biology Programme, Centro Nacional de Investigaciones Oncologicas (CNIO), Madrid, Spain activation by the Hh pathway requires the histone acetyltrans- ferase (HAT) PCAF. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Materials and Methods Corresponding Author: Kristian Helin, BRIC, University of Copenhagen, Ole Maaløes Vej 5, DK-2200 Copenhagen N. Phone: 45-35-32-56-66; Fax: Cell culture and reagents 45-35-32-56-69; E-mail: [email protected] Human cell lines (U87, U118, T98G, and Daoy) were doi: 10.1158/0008-5472.CAN-12-4660 purchased from the American Type Culture Collection Ó2013 American Association for Cancer Research. (ATCC) and used at low passage numbers. A short tandem www.aacrjournals.org OF1 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 2013 American Association for Cancer Research. Published OnlineFirst August 13, 2013; DOI: 10.1158/0008-5472.CAN-12-4660 Malatesta et al. repeat profile was done by the ATTC, and the cells tested entire statistical analysis was conducted using the statisti- negative for mycoplasm. 293-ShhN and NIH3T3 cells were cal software 'R'. kindlyprovidedbyDr.J.Taipale(KarolinskaInstitute,Stock- holm, Sweden) and grown as previously described (18). Cells RNA extraction and gene expression analysis were maintained at 37 Cand5%CO2 in Dulbecco's Modified Total RNA was isolated using the RNAeasy Mini Kit (Qiagen) Eagle's Medium (DMEM) supplemented with 100 mg/mL according to the manufacturer's instructions. cDNA was syn- penicillin, 100 mg/mL streptomycin, and 10% FBS (Gibco; thesized using the TaqMan Reverse Transcription Kit (Applied U87, U118, T98G, DAOY, and 293-ShhN) or 10% newborn calf Biosystems). Quantitative PCR (qPCR) was conducted using serum (NIH3T3). GBM543 neurospheres were isolated from SYBR Green PCR Master Mix (Applied Biosystems) on an ABI patients suffering from glioblastoma (GBM) and propagated Prism 7300 Real-Time PCR system (Applied Biosystems) or on as previously described (19). Ink4a-Arf-nullneuralstemcells a LightCycler 480 System (Roche Applied Science), using the (NSC) were isolated and grown as previously described (20). LightCycler 480 SYBR Green I Master Mix (Roche Applied Viral transductions were conducted using pLKO vectors. Science) according to the manufacturer's instructions. Error The different target sequences are available in Supplemen- bars represent SD of three PCR amplifications for each sample. tary Table S1. Cells were transduced with lentiviral particles Similar results were obtained in at least three independent for 16 hours, and selected with 2 mg/mL puromycin (Invi- experiments. The qPCR primers are available in Supplemen- trogen) 48 hours after transduction. Treatments using SAG tary Table S2. (ALX-270-426-M001 Alexis), cyclopamine (C4116 SIGMA), or anacardic acid (AA; G5173 SIGMA) were carried out 24 hours Immunoblotting and immunoprecipitation after cell plating or as indicated. To prepare whole-cell extracts for immunoblotting analysis, For cell proliferation assays, cells were seeded at two dif- cells were lysed in high salt buffer S300P (50 mmol/L Tris–HCl, ferent densities into 96-well plates (Nunc#161093) and three 300 mmol/L NaCl, 0.5% Igepal, 1 mmol/L EDTA, 1 mmol/L images per well were acquired every hour over a period of three DTT, 1 mmol/L phenylmethylsulfonylfluoride (PMSF), 1 mg/mL to five days using the Incucyte Zoom (Essen Biosciences). leupeptin, and 1 mg/mL aprotinin). For immunoprecipitations, Image analysis was conducted using the Incucyte Zoom soft- protein A/G-agarose beads (GE Healthcare) were pre-coupled ware package. O/N with the indicated antibodies. Equal amounts of protein lysates (S300P buffer) were used for each immunoprecipita- siRNA screening and luciferase assay tion. Immunoprecipitates were eluted from beads and ana- The screening was done on a customized siRNA library lyzed by immunoblotting with the indicated antibodies. The against 17 different mouse acetyltransferases, with each gene identity and the suppliers of the antibodies are provided in represented by three independent siRNA constructs (Sigma). Supplementary Table S3. The different target sequences are described in Supplementary Table S1. In addition, each plate contained four nontargeting Chromatin immunoprecipitation assay controls and four siRNAs against Smo as positive controls. The Chromatin immunoprecipitation (ChIP) was carried out as automated screening was done using a MicrolabSTAR liquid described previously (23). For each immunoprecipitation, 0.5 handling system (Hamilton Robotics). NIH3T3 reporter cells to 1 mg of chromatin was used except for histones and histone (21) were reverse transfected with the customized siRNA modifications where 100 mg were used. The qPCR primers are library including individual positive and negative controls available in Supplementary Table S2, and the antibodies in using Lipofectamine 2000 (Invitrogen) according to the man- Supplementary Table S3. ufacturer's instructions. After 24 hours of transfection, the medium was changed to conditioned medium containing Orthotopic transplantation À/À Sonic Hedgehog protein (Shh; derived from 293-ShhN cells) Transformed NSCs [tNSC, Ink4a-Arf NSCs expressing or respective culture medium and incubated for another 48 constitutively
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