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  • Oncogenomics
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Identification of novel androgen response genes in prostate cancer cells by coupling chromatin immunoprecipitation and genomic microarray analysis

Oncogene volume 26, pages 4453–4463 (2007)Cite this article

Abstract

The androgen receptor (AR) plays a key role as a transcriptional factor in prostate development and carcinogenesis. Identification of androgen-regulated genes is essential to elucidate the AR pathophysiology in prostate cancer. Here, we identified androgen target genes that are directly regulated by AR in LNCaP cells, by combining chromatin immunoprecipitation (ChIP) with tiling microarrays (ChIP-chip). ChIP-enriched or control DNAs from the cells treated with R1881 were hybridized with the ENCODE array, in which a set of regions representing approximately 1% of the whole genome. We chose 10 bona fide AR-binding sites (ARBSs) (P<1e-5) and validated their significant AR recruitment ligand dependently. Eight upregulated genes by R1881 were identified in the vicinity of the ARBSs. Among the upregulated genes, we focused on UGT1A and CDH2 as AR target genes, because the ARBSs close to these genes (in UGT1A distal promoter and CDH2 intron 1) were most significantly associated with acetylated histone H3/H4, RNA polymerase II and p160 family co-activators. Luciferase reporter constructs including those two ARBSs exhibited ligand-dependent transcriptional regulator/enhancer activities. The present study would be powerful to extend our knowledge of the diversity of androgen genetic network and steroid action in prostate cancer cells.

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References

  • Bernstein BE, Kamal M, Lindblad-Toh K, Bekiranov S, Bailey DK, Huebert DJ et al. (2005). Genomic maps and comparative analysis of histone modifications in human and mouse. Cell 120: 169–181.

    Article  CAS  Google Scholar 

  • Carroll JS, Liu XS, Brodsky AS, Li W, Meyer CA, Szary AJ et al. (2005). Chromosome-wide mapping of estrogen receptor binding reveals long-range regulation requiring the forkhead protein FoxA1. Cell 122: 33–43.

    Article  CAS  Google Scholar 

  • Cawley S, Bekiranov S, Ng HH, Kapranov P, Sekinger EA, Kampa D et al. (2004). Unbiased mapping of transcription factor binding sites along human chromosomes 21 and 22 points to widespread regulation of noncoding RNAs. Cell 116: 499–509.

    Article  CAS  Google Scholar 

  • Chen CD, Welsbie DS, Tran C, Baek SH, Chen R, Vessella R et al. (2004). Molecular determinants of resistance to antiandrogen therapy. Nat Med 10: 33–39.

    Article  Google Scholar 

  • Chen S, Beaton D, Nguyen N, Senekeo-Effenberger K, Brace-Sinnokrak E, Argikar U et al. (2005). Tissue-specific, inducible, and hormonal control of the human UDP-glucuronosyltransferase-1 (UGT1) locus. J Biol Chem 280: 37547–37557.

    Article  CAS  Google Scholar 

  • Chene L, Giroud C, Desgrandchamps F, Boccon-Gibod L, Cussenot O, Berthon P et al. (2004). Extensive analysis of the 7q31 region in human prostate tumors supports TES as the best candidate tumor suppressor gene. Int J Cancer 111: 798–804.

    Article  CAS  Google Scholar 

  • Cooper CS, Park M, Blair DG, Tainsky MA, Huebner K, Croce CM et al. (1984). Molecular cloning of a new transforming gene from a chemically transformed human cell line. Nature 311: 29–33.

    Article  CAS  Google Scholar 

  • Coutts AS, MacKenzie E, Griffith E, Black DM . (2003). TES is a novel focal adhesion protein with a role in cell spreading. J Cell Sci 116: 897–906.

    Article  CAS  Google Scholar 

  • Diaz M, Rodriguez JC, Sanchez J, Sanchez MT, Martin A, Merino AM et al. (2002). Clinical significance of pepsinogen C tumor expression in patients with stage D2 prostate carcinoma. Int J Biol Markers 17: 125–129.

    Article  CAS  Google Scholar 

  • Duguay Y, McGrath M, Lepine J, Gagne JF, Hankinson SE, Colditz GA et al. (2004). The functional UGT1A1 promoter polymorphism decreases endometrial cancer risk. Cancer Res 64: 1202–1207.

    Article  CAS  Google Scholar 

  • ENCODE Project Consortium, EP (2004). The ENCODE (ENCyclopedia of DNA Elements) Project. Science 306: 636–640.

    Article  Google Scholar 

  • Giuliani L, Ciotti M, Stoppacciaro A, Pasquini A, Silvestri I, De Matteis A et al. (2005). UDP-glucuronosyltransferases 1A expression in human urinary bladder and colon cancer by immunohistochemistry. Oncol Rep 13: 185–191.

    CAS  PubMed  Google Scholar 

  • Gong QH, Cho JW, Huang T, Potter C, Gholami N, Basu NK et al. (2001). Thirteen UDP glucuronosyltransferase genes are encoded at the human UGT1 gene complex locus. Pharmacogenetics 11: 357–368.

    Article  CAS  Google Scholar 

  • Grossmann ME, Huang H, Tindall DJ . (2001). Androgen receptor signaling in androgen-refractory prostate cancer. J Natl Cancer Inst 93: 1687–1697.

    Article  CAS  Google Scholar 

  • Harrington WR, Sengupta S, Katzenellenbogen BS . (2006). Estrogen regulation of the glucuronidation enzyme UGT2B15 in estrogen receptor-positive breast cancer cells. Endocrinology 147: 3843–3850.

    Article  CAS  Google Scholar 

  • Hazan RB, Kang L, Whooley BP, Borgen PI . (1997). N-cadherin promotes adhesion between invasive breast cancer cells and the stroma. Cell Adhes Commun 4: 399–411.

    Article  CAS  Google Scholar 

  • Horie-Inoue K, Bono H, Okazaki Y, Inoue S . (2004). Identification and functional analysis of consensus androgen response elements in human prostate cancer cells. Biochem Biophys Res Commun 325: 1312–1317.

    Article  CAS  Google Scholar 

  • Horie-Inoue K, Takayama K, Bono HU, Ouchi Y, Okazaki Y, Inoue S . (2006). Identification of novel steroid target genes through the combination of bioinformatics and functional analysis of hormone response elements. Biochem Biophys Res Commun 339: 99–106.

    Article  CAS  Google Scholar 

  • Humphrey PA, Zhu X, Zarnegar R, Swanson PE, Ratliff TL, Vollmer RT et al. (1995). Hepatocyte growth factor and its receptor (c-MET) in prostatic carcinoma. Am J Pathol 147: 386–396.

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jaggi M, Nazemi T, Abrahams NA, Baker JJ, Galich A, Smith LM et al. (2006). N-cadherin switching occurs in high Gleason grade prostate cancer. Prostate 66: 193–199.

    Article  CAS  Google Scholar 

  • Katou Y, Kaneshiro K, Aburatani H, Shirahige K . (2006). Genomic approach for the understanding of dynamic aspect of chromosome behavior. Methods Enzymol 409: 389–410.

    Article  CAS  Google Scholar 

  • Kawana Y, Ichikawa T, Suzuki H, Ueda T, Komiya A, Ichikawa Y et al. (2002). Loss of heterozygosity at 7q31.1 and 12p13-12 in advanced prostate cancer. Prostate 53: 60–64.

    Article  CAS  Google Scholar 

  • Kent WJ, Sugnet CW, Furey TS, Roskin KM, Pringle TH, Zahler AM et al. (2002). The human genome browser at UCSC. Genome Res 12: 996–1006.

    Article  CAS  Google Scholar 

  • Laganière J, Deblois G, Lefebvre C, Bataille AR, Robert F, Giguère V . (2005). From the cover: location analysis of estrogen receptor alpha target promoters reveals that FOXA1 defines a domain of the estrogen response. Proc Natl Acad Sci USA 102: 11651–11656.

    Article  Google Scholar 

  • Lepine J, Bernard O, Plante M, Tetu B, Pelletier G, Labrie F et al. (2004). Specificity and regioselectivity of the conjugation of estradiol, estrone, and their catecholestrogen and methoxyestrogen metabolites by human uridine diphospho-glucuronosyltransferases expressed in endometrium. J Clin Endocrinol Metab 89: 5222–5232.

    Article  CAS  Google Scholar 

  • Maeda A, Nakashiro K, Hara S, Sasaki T, Miwa Y, Tanji N et al. (2006). Inactivation of AR activates HGF/c-Met system in human prostatic carcinoma cells. Biochem Biophys Res Commun 347: 1158–1165.

    Article  CAS  Google Scholar 

  • Matys V, Fricke E, Geffers R, Gossling E, Haubrock M, Hehl R et al. (2003). TRANSFAC: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 31: 374–378.

    Article  CAS  Google Scholar 

  • Monks DA, Watson NV . (2001). N-cadherin expression in motoneurons is directly regulated by androgens: a genetic mosaic analysis in rats. Brain Res 895: 73–79.

    Article  CAS  Google Scholar 

  • Ogawa H, Inouye S, Tsuji FI, Yasuda K, Umesono K . (1995). Localization, trafficking, and temperature-dependence of the Aequorea green fluorescent protein in cultured vertebrate cells. Proc Natl Acad Sci USA 92: 11899–11903.

    Article  CAS  Google Scholar 

  • Pisters LL, Troncoso P, Zhau HE, Li W, von Eschenbach AC, Chung LW . (1995). c-met Proto-oncogene expression in benign and malignant human prostate tissues. J Urol 154: 293–298.

    Article  CAS  Google Scholar 

  • Porkka KP, Helenius MA, Visakorpi T . (2002). Cloning and characterization of a novel six-transmembrane protein STEAP2, expressed in normal and malignant prostate. Lab Invest 82: 1573–1582.

    Article  CAS  Google Scholar 

  • Sandelin A, Alkema W, Engstrom P, Wasserman WW, Lenhard B . (2004). JASPAR: an open-access database for eukaryotic transcription factor binding profiles. Nucleic Acids Res 32: D91–94.

    Article  CAS  Google Scholar 

  • Shang Y, Brown M . (2002). Molecular determinants for the tissue specificity of SERMs. Science 295: 2465–2468.

    Article  CAS  Google Scholar 

  • Shang Y, Myers M, Brown M . (2002). Formation of the androgen receptor transcription complex. Mol Cell 9: 601–610.

    Article  CAS  Google Scholar 

  • Strassburg CP, Manns MP, Tukey RH . (1997). Differential down-regulation of the UDP-glucuronosyltransferase 1A locus is an early event in human liver and biliary cancer. Cancer Res 57: 2979–2985.

    CAS  PubMed  Google Scholar 

  • Sugatani J, Kojima H, Ueda A, Kakizaki S, Yoshinari K, Gong QH et al. (2001). The phenobarbital response enhancer module in the human bilirubin UDP-glucuronosyltransferase UGT1A1 gene and regulation by the nuclear receptor CAR. Hepatology 33: 1232–1238.

    Article  CAS  Google Scholar 

  • Tobias ES, Hurlstone AF, MacKenzie E, McFarlane R, Black DM . (2001). The TES gene at 7q31.1 is methylated in tumours and encodes a novel growth-suppressing LIM domain protein. Oncogene 20: 2844–2853.

    Article  CAS  Google Scholar 

  • Tomita K, van Bokhoven A, van Leenders GJ, Ruijter ET, Jansen CF, Bussemakers MJ et al. (2000). Cadherin switching in human prostate cancer progression. Cancer Res 60: 3650–3654.

    CAS  PubMed  Google Scholar 

  • Wang Q, Carroll JS, Brown M . (2005). Spatial and temporal recruitment of androgen receptor and its coactivators involves chromosomal looping and polymerase tracking. Mol Cell 19: 631–642.

    Article  CAS  Google Scholar 

  • Xie W, Yeuh MF, Radominska-Pandya A, Saini SP, Negishi Y, Bottroff BS et al. (2003). Control of steroid, heme, and carcinogen metabolism by nuclear pregnane X receptor and constitutive androstane receptor. Proc Natl Acad Sci USA 100: 4150–4155.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank T Suzuki and R Nozawa for their technical assistance. This work was supported in part by grants-in-aid from the Ministry of Health, Labor and Welfare; from the Japan Society for the Promotion of Science; from The Promotion and Mutual Aid Corporation for Private Schools of Japan. This work was supported in part by a grant of the Genome Network Project from the Ministry of Education, Culture, Sports, Science and Technology.

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Authors and Affiliations

  1. Department of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

    K Takayama, T Urano, Y Ouchi & S Inoue

  2. Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan

    K Kaneshiro, S Tsutsumi & H Aburatani

  3. Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan

    K Takayama, K Horie-Inoue, K Ikeda, T Urano, N Ijichi & S Inoue

  4. Division for Gene Research, Center for Biological Resources and Informatics, Tokyo Institute of Technology, Tokyo, Japan

    K Shirahige

  5. CREST, Japan Science and Technology Agency (JST), Tokyo, Japan

    H Aburatani

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  1. K Takayama
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Correspondence to S Inoue.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Takayama, K., Kaneshiro, K., Tsutsumi, S. et al. Identification of novel androgen response genes in prostate cancer cells by coupling chromatin immunoprecipitation and genomic microarray analysis. Oncogene 26, 4453–4463 (2007). https://doi.org/10.1038/sj.onc.1210229

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