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Expression, regulation and function of the ISGylation system in prostate cancer

Oncogene volume 28, pages 2606–2620 (2009)Cite this article

Abstract

The androgen receptor (AR) plays a crucial role in the modulation of prostate cell proliferation and is involved in the development and progression of prostate cancer (PCa). An understanding of the complex regulation of AR provides novel treatment options for PCa. Here, we show (i) that the ubiquitin-like modifier, interferon-stimulated gene 15 (ISG15), and most enzymes involved in ISG15 conjugation were upregulated in tumor samples versus in non-malignant tissues of PCa patients and (ii) that the expression of these components significantly differed between tumors in patients treated with and without androgen ablation. Using PCa cell lines as in vitro models, the specific androgen-mediated, AR-dependent regulation of the ISGylation components was confirmed. In addition, the ISGylation system controls AR mRNA and protein expressions, as overexpression of Ube1L as a limiting ISGylation factor in the AR+ androgen-sensitive PCa cell line, LNCaP, results in significant AR upregulation, accompanied by an increased proliferation even under androgen deprivation. Accordingly, Ube1L knockdown decreased the AR expression. Thus, this study describes for the first time the modulation of AR expression by ISGylation components, which affects the proliferation of PCa cells, thereby providing evidence for a novel function of the ISGylation system in malignant transformation.

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References

  • Andersen JB, Aaboe M, Borden EC, Goloubeva OG, Hassel BA, Orntoft TF . (2006). Stage-associated overexpression of the ubiquitin-like protein, ISG15, in bladder cancer. Br J Cancer 94: 1465–1471.

    Article  CAS  Google Scholar 

  • Andersen JB, Hassel BA . (2006). The interferon regulated ubiquitin-like protein, ISG15, in tumorigenesis: friend or foe? Cytokine Growth Factor Rev 17: 411–421.

    Article  CAS  Google Scholar 

  • Asirvatham AJ, Schmidt M, Gao B, Chaudhary J . (2006). Androgens regulate the immune/inflammatory response and cell survival pathways in rat ventral prostate epithelial cells. Endocrinol 147: 257–271.

    Article  CAS  Google Scholar 

  • Basrawala Z, Alimirah F, Xin H, Mohideen N, Campbell SC, Flanigan RC et al. (2006). Androgen receptor levels are increased by interferons in human prostate stromal and epithelial cells. Oncogene 25: 2812–2817.

    Article  CAS  Google Scholar 

  • Bektas N, Noetzel E, Veeck J, Press MF, Kristiansen G, Naami A et al. (2008). The ubiquitin-like molecule interferon-stimulated gene 15 (ISG15) is a potential prognostic marker in human breast cancer. Breast Cancer Res 10: R58.

    Article  Google Scholar 

  • Berger R, Febbo PG, Majumder PK, Zhao JJ, Mukherjee S, Signoretti S et al. (2004). Androgen-induced differentiation and tumorigenicity of human prostate epithelial cells. Cancer Res 64: 8867–8875.

    Article  CAS  Google Scholar 

  • Van Bokhoven A, Varella-Garcia M, Korch C, Johannes WU, Smith EE, Miller HL et al. (2003). Molecular characterization of human prostate carcinoma cell lines. Prostate 57: 205–225.

    Article  CAS  Google Scholar 

  • Borden EC, Lindner D, Dreicer R, Hussein M, Peereboom D . (2000). Second-generation interferons for cancer: clinical targets. Semin Cancer Biol 10: 125–144.

    Article  CAS  Google Scholar 

  • Callewaert L, Verrijdt G, Haelens A, Claessens F . (2004). Differential effect of small ubiquitin-like modifier (SUMO)-ylation of the androgen receptor in the control of cooperativity on selective versus canonical response elements. Mol Endocrinol 18: 1438–1449.

    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 

  • Craft N, Shostak Y, Carey M, Sawyers CL . (1999). A mechanism for hormone-independent prostate cancer through modulation of androgen receptor signaling by the HER-2/neu tyrosine kinase. Nat Med 5: 280–285.

    Article  CAS  Google Scholar 

  • Culig Z, Hobisch A, Herold M, Hittmair A, Thurnher M, Eder IE et al. (1998). Interleukin 1beta mediates the modulatory effects of monocytes on LNCaP human prostate cancer cells. Br J Cancer 78: 1004–1011.

    Article  CAS  Google Scholar 

  • Dastur A, Beaudenon S, Kelley M, Krug RM, Huibregtse JM . (2006). Herc5, an interferon-induced HECT E3 enzyme, is required for conjugation of ISG15 in human cells. J Biol Chem 281: 4334–4338.

    Article  CAS  Google Scholar 

  • Desai KV, Michalowska AM, Kondaiah P, Ward JM, Shih JH, Green JE . (2004). Gene expression profiling identifies a unique androgen-mediated inflammatory/immune signature and a PTEN (phosphatase and tensin homolog deleted on chromosome 10)-mediated apoptotic response specific to the rat ventral prostate. Mol Endocrinol 18: 2895–2907.

    Article  CAS  Google Scholar 

  • Desai SD, Haas AL, Wood LM, Tsai YC, Pestka S, Rubin EH et al. (2006). Elevated expression of ISG15 in tumor cells interferes with the ubiquitin/26S proteasome pathway. Cancer Res 66: 921–928.

    Article  CAS  Google Scholar 

  • Desai SD, Wood LM, Tsai YC, Hsieh TS, Marks JR, Scott GL et al. (2008). ISG15 as a novel tumor biomarker for drug sensitivity. Mol Cancer Ther 7: 1430–1439.

    Article  CAS  Google Scholar 

  • Edwards J, Krishna NS, Grigor KM, Bartlett JM . (2003). Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer. Br J Cancer 89: 552–556.

    Article  CAS  Google Scholar 

  • Feng Q, Sekula D, Guo Y, Liu X, Black CC, Galimberti F et al. (2008). UBE1L causes lung cancer growth suppression by targeting cyclin D1. Mol Cancer Ther 7: 3780–3788.

    Article  CAS  Google Scholar 

  • Giannakopoulos NV, Luo JK, Papov V, Zou W, Lenschow DJ, Jacobs BS et al. (2005). Proteomic identification of proteins conjugated to ISG15 in mouse and human cells. Biochem Biophys Res Commun 336: 496–506.

    Article  CAS  Google Scholar 

  • Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD et al. (2002). Androgen receptor phosphorylation. Regulation and identification of phosphorylation sites. J Biol Chem 277: 29304–29314.

    Article  CAS  Google Scholar 

  • Gong Y, Blok LJ, Perry JE, Lindzey JK, Tindall DJ . (1995). Calcium regulation of androgen receptor expression in the human prostate cancer cell line LNCaP. Endocrinology 136: 2172–2178.

    Article  CAS  Google Scholar 

  • Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS et al. (2001b). A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen-deprivation therapy. Cancer Res 61: 4315–4319.

    CAS  Google Scholar 

  • Gregory CW, Johnson Jr RT, Mohler JL, French FS, Wilson EM . (2001a). Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res 61: 2892–2898.

    CAS  PubMed  Google Scholar 

  • Heemers HV, Tindall DJ . (2007). Androgen receptor (AR) coregulators: a diversity of functions converging on and regulating the AR transcriptional complex. Endocr Rev 28: 778–808.

    Article  CAS  Google Scholar 

  • Iacobuzio-Donahue CA, Maitra A, Olsen M, Lowe AW, van Heek NT, Rosty C et al. (2003). Exploration of global gene expression patterns in pancreatic adenocarcinoma using cDNA microarrays. Am J Pathol 162: 1151–1162.

    Article  CAS  Google Scholar 

  • Ikeda K, Orimo A, Higashi Y, Muramatsu M, Inoue S . (2000). Efp as a primary estrogen-responsive gene in human breast cancer. FEBS Lett 472: 9–13.

    Article  CAS  Google Scholar 

  • Jemal A, Siegel R, Ward E, Hao Y, Xu J, Murray T et al. (2008). Cancer statistics, 2008. CA Cancer J Clin 58: 71–96.

    Article  Google Scholar 

  • Jung D, Hilmes C, Knuth A, Jaeger E, Huber C, Seliger B . (1999). Gene transfer of the Co-stimulatory molecules B7-1 and B7-2 enhances the immunogenicity of human renal cell carcinoma to a different extent. Scand J Immunol 50: 242–249.

    Article  CAS  Google Scholar 

  • Kalvakolanu DV . (2000). Interferons and cell growth control. Histol Histopathol 15: 523–537.

    CAS  PubMed  Google Scholar 

  • Kim KI, Giannakopoulos NV, Virgin HW, Zhang DE . (2004). Interferon-inducible ubiquitin E2, Ubc8, is a conjugating enzyme for protein ISGylation. Mol Cell Biol 24: 9592–9600.

    Article  CAS  Google Scholar 

  • Khodarev NN, Minn AJ, Efimova EV, Darga TE, Labay E, Beckett M et al. (2007). Signal transducer and activator of transcription 1 regulates both cytotoxic and prosurvival functions in tumor cells. Cancer Res 67: 9214–9220.

    Article  CAS  Google Scholar 

  • Ko S, Shi L, Kim S, Song CS, Chatterjee B . (2008). Interplay of nuclear factor-kappaB and B-myb in the negative regulation of androgen receptor expression by tumor necrosis factor alpha. Mol Endocrinol 22: 273–286.

    Article  CAS  Google Scholar 

  • Korant BD, Blomstrom DC, Jonak GJ, Knight Jr E . (1984). Interferon-induced proteins. Purification and characterization of a 15 000-dalton protein from human and bovine cells induced by interferon. J Biol Chem 259: 14835–14839.

    CAS  PubMed  Google Scholar 

  • Li R, Wheeler T, Dai H, Frolov A, Thompson T, Ayala G . (2004). High level of androgen receptor is associated with aggressive clinicopathologic features and decreased biochemical recurrence-free survival in prostate: cancer patients treated with radical prostatectomy. Am J Surg Pathol 28: 928–934.

    Article  Google Scholar 

  • Lin DL, Whitney MC, Yao Z, Keller ET . (2001). Interleukin-6 induces androgen responsiveness in prostate cancer cells through up-regulation of androgen receptor expression. Clin Cancer Res 7: 1773–1781.

    CAS  PubMed  Google Scholar 

  • Linja MJ, Savinainen KJ, Saramäki OR, Tammela TL, Vessella RL, Visakorpi T . (2001). Amplification and overexpression of androgen receptor gene in hormone-refractory prostate cancer. Cancer Res 61: 3550–3555.

    CAS  Google Scholar 

  • Liu M, Hummer BT, Li X, Hassel BA . (2004). Camptothecin induces the ubiquitin-like protein, ISG15, and enhances ISG15 conjugation in response to interferon. J Interferon Cytokine Res 24: 647–654.

    Article  CAS  Google Scholar 

  • Maggiolini M, Recchia AG, Carpino A, Vivacqua A, Fasanella G, Rago V et al. (2004). Oestrogen receptor beta is required for androgen-stimulated proliferation of LNCaP prostate cancer cells. Mol Endocrinol 32: 777–791.

    Article  CAS  Google Scholar 

  • Malakhov MP, Kim KI, Malakhova OA, Jacobs BS, Borden EC, Zhang DE. (2003). High-throughput immunoblotting. Ubiquitin-like protein ISG15 modifies key regulators of signal transduction. J Biol Chem 278: 16608–16613.

    Article  CAS  Google Scholar 

  • Malakhova OA, Zhang DE . (2008). ISG15 inhibits Nedd4 ubiquitin E3 activity and enhances the innate antiviral response. J Biol Chem 283: 8783–8787.

    Article  CAS  Google Scholar 

  • Mitsui K, Nakanisha M, Ohtsuka S, Norwood TH, Okabayashi K, Miyamoto C et al. (1999). A novel human gene encoding HECT domain and RCC1-like repeats interacts with cyclins and is potentially regulated by the tumor suppressor proteins. Biochem Biophys Res Commun 266: 115–122.

    Article  CAS  Google Scholar 

  • Nakajima A, Maruyama S, Bohgaki M, Miyajima N, Tsukiyama T, Sakuragi N et al. (2007). Ligand-dependent transcription of estrogen receptor alpha is mediated by the ubiquitin ligase EFP. Biochem Biophys Res Commun 357: 245–251.

    Article  CAS  Google Scholar 

  • Nantermet PV, Xu J, Yu Y, Hodor P, Holder D, Adamski S et al. (2004). Identification of genetic pathways activated by the androgen receptor during the induction of proliferation in the ventral prostate gland. J Biol Chem 279: 1310–1322.

    Article  CAS  Google Scholar 

  • Okumura F, Zou W, Zhang DE . (2007). ISG15 modification of the eIF4E cognate 4EHP enhances cap structure-binding activity of 4EHP. Genes Dev 21: 255–260.

    Article  CAS  Google Scholar 

  • Olshavsky NA, Groh EM, Comstock CE, Morey LM, Wang Y, Revelo MP et al. (2008). Cyclin D3 action in androgen receptor regulation and prostate cancer. Oncogene 27: 3111–3121.

    Article  CAS  Google Scholar 

  • Pitterle DM, Jolicoeur EM, Bepler G . (1998). Hot spots for molecular genetic alternations in lung cancer. In vivo 12: 643–658.

    CAS  PubMed  Google Scholar 

  • Polyak K, Xia Y, Zweier JL, Kinzler KW, Vogelstein B . (1997). A model for p53-induced apoptosis. Nature 389: 300–305.

    Article  CAS  Google Scholar 

  • Reddy GP, Barrack ER, Dou QP, Menon M, Pelley R, Sarkar FH et al. (2006). Regulatory processes affecting androgen receptor expression, stability, and function: potential targets to treat hormone-refractory prostate cancer. J Cell Biochem 98: 1408–1423.

    Article  CAS  Google Scholar 

  • Rokhlin OW, Taghiyev AF, Guseva NV, Glover RA, Chumakov PM, Kravchenko JE et al. (2005). Androgen regulates apoptosis induced by TNFR family ligands via multiple signalling pathways in LNCaP. Oncogene 24: 6773–6784.

    Article  CAS  Google Scholar 

  • Sakuma M, Akahira J, Suzuki T, Inoue S, Ito K, Moriya T et al. (2005). Expression of estrogen-responsive finger protein (Efp) is associated with advanced disease in human epithelial ovarian cancer. Gynecol Oncol 99: 664–670.

    Article  CAS  Google Scholar 

  • Sica G, Dell’Acqua G, Iacopino F, Fattorossi A, Marchetti P, van der Kwast TH et al. (1994). Androgen receptors and hormone sensitivity of a human prostatic cancer cell line (PC-3) are modulated by natural β-interferon. Urol Res 22: 33–38.

    Article  CAS  Google Scholar 

  • Stanbrough M, Leav I, Kwan PW, Bubley GJ, Balk SP . (2001). Prostatic intraepithelial neoplasia in mice expressing an androgen receptor transgene in prostate epithelium. Proc Natl Acad Sci USA 98: 10823–10828.

    Article  CAS  Google Scholar 

  • Suzuki T, Urano T, Tsukui T, Horie-Inoue K, Moriya T, Ishida T et al. (2005). Estrogen-responsive finger protein as a new potential biomarker for breast cancer. Clin Cancer Res 11: 6148–6154.

    Article  CAS  Google Scholar 

  • Takahashi Y, Perkins SN, Hursting SD, Wang TTY . (2007). 17β-estradiol differentially regulates androgen-responsive genes through estrogen receptor-β- and extracellular-signal regulated kinase-dependent pathways in LNCaP human prostate cancer cells. Mol Carcinog 46: 117–129.

    Article  CAS  Google Scholar 

  • Takeuchi T, Iwahara S, Saeki Y, Sasajima H, Yokosawa H . (2005). Link between the ubiquitin conjugation system and the ISG15 conjugation system: ISG15 conjugation to the UbcH6 ubiquitin E2 enzyme. J Biochem (Tokyo) 138: 711–719.

    Article  CAS  Google Scholar 

  • Takeuchi T, Kobayashi T, Tamura S, Yokosawa H . (2006). Negative regulation of protein phosphatase 2Cbeta by ISG15 conjugation. FEBS Lett 580: 4521–4526.

    Article  CAS  Google Scholar 

  • Takeuchi T, Yokosawa H . (2005). ISG15 modification of Ubc13 suppresses its ubiquitin-conjugating activity. Biochem Biophys Res Commun 336: 9–13.

    Article  CAS  Google Scholar 

  • Taplin ME, Balk SP . (2004). Androgen receptor: a key molecule in the progression of prostate cancer to hormone independence. J Cell Biol 91: 483–490.

    CAS  Google Scholar 

  • Weichselbaum RR, Ishwaran H, Yoon T, Nuyten DS, Baker SW, Khodarev N et al. (2008). An interferon-related gene signature for DNA damage resistance is a predictive marker for chemotherapy and radiation for breast cancer. Proc Natl Acad Sci USA 105: 18490–18495.

    Article  CAS  Google Scholar 

  • Yeap BB, Krueger RG, Leedman PJ . (1999). Differential posttranscriptional regulation of androgen receptor gene expression by androgen in prostate and breast cancer cells. Endocrinology 140: 3282–3291.

    Article  CAS  Google Scholar 

  • Yuan W, Krug RM . (2001). Influenza B virus NS1 protein inhibits conjugation of the interferon (IFN)-induced ubiquitin-like ISG15 protein. EMBO J 20: 362–371.

    Article  CAS  Google Scholar 

  • Zhao C, Beaudenon SL, Kelley ML, Waddell MB, Yuan W, Schulman BA et al. (2004). The UbcH8 ubiquitin E2 enzyme is also the E2 enzyme for ISG15, an IFN-alpha/beta-induced ubiquitin-like protein. Proc Natl Acad Sci USA 101: 7578–7582.

    Article  CAS  Google Scholar 

  • Zhao C, Denison C, Huibregtse JM, Gygi S, Krug RM . (2005). Human ISG15 conjugation targets both IFN-induced and constitutively expressed proteins functioning in diverse cellular pathways. Proc Natl Acad Sci USA 102: 10200–10205.

    Article  CAS  Google Scholar 

  • Zou W, Wang J, Zhang DE . (2007). Negative regulation of ISG15 E3 ligase EFP through its autoISGylation. Biochem Biophys Res Commun 354: 321–327.

    Article  CAS  Google Scholar 

  • Zou W, Zhang DE . (2006). The interferon-inducible ubiquitin-protein isopeptide ligase (E3) EFP also functions as an ISG15 E3 ligase. J Biol Chem 281: 3989–3994.

    Article  CAS  Google Scholar 

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  1. A Kiessling

    Present address: 4Present address: Novartis Pharma AG, Basel 4057, Switzerland,

Authors and Affiliations

  1. Medical Faculty, Institute for Medical Immunology, Martin-Luther-University Halle-Wittenberg, Halle, Germany

    A Kiessling, C Hogrefe, S Erb & B Seliger

  2. Department of Bioorganic Chemistry, Leibniz Institute of Plant Biochemistry, Halle, Germany

    C Bobach & L Wessjohann

  3. Department of Urology, Medical Faculty Carl Gustav Carus, Technical University of Dresden, Dresden, Germany

    S Fuessel

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Kiessling, A., Hogrefe, C., Erb, S. et al. Expression, regulation and function of the ISGylation system in prostate cancer. Oncogene 28, 2606–2620 (2009). https://doi.org/10.1038/onc.2009.115

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