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Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line

Oncogene volume 23, pages 5175–5184 (2004)Cite this article

Abstract

Androgen receptor (AR) overexpression is one of the characteristics of prostate cancer (PC) that progresses to hormone independence. An androgen-independent (AI) derivative, with much higher AR-mRNA and protein levels than the parental LNCaP cell line, whose proliferation was androgen dependent (AD), was used to explore the mechanism of AR overexpression. We found that a suppressor element (ARS), previously identified in mouse AR and located in the 5′-untranslated region of human AR gene, malfunctions in AI cells. Transfection of constructs that included ARS element into AD cells reduced the transactivating activities of both AR promoter and a heterologous SV40 promoter. The deletion of ARS resulted in an eightfold increase in AR-promoter activity in AD cells, but had no effect in AI cells. Moreover, the nuclear extracts of AD cells contained proteins that produced a specific, ARS-binding complex, while this complex appeared to have been lost from AI cells. Most importantly, treatment of AI cells with a demethylating agent or histone deacetylase inhibitors restored the lost ARS-binding complex. The restoration of the complex coincided with a reduced expression of AR-mRNA and protein and a reduced rate of AR-gene transcription, determined by nuclear run-on experiment. Thus, epigenetic transcriptional silencing of the suppressor protein(s) may be responsible for AR overexpression in AI cells, and its reversal in hormone-independent PC may normalize AR levels and restore their hormone dependence.

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References

  • Banerjee PP, Banerjee S and Brown TR . (2001). Endocrinology, 142, 4066–4075.

  • Baxevanis AD . (2002). Nucleic Acids Res., 30, 1–12.

  • Blok LJ, Themmen AP, Peters AH, Trapman J, Baarends WM, Hoogerbrugge JW and Grootegoed JA . (1992). Mol. Cell. Endocrinol., 88, 153–164.

  • Bouwman P and Philipsen S . (2002). Mol. Cell. Endocrinol., 195, 27–38.

  • Bruchovsky N, Rennie PS, Coldman AJ, Goldenberg SL, To M and Lawson D . (1990). Cancer Res., 50, 2275–2282.

  • Buetter R . (1994). Gene Bank.

  • Cameron EE, Bachman KE, Myohanen S, Herman JG and Baylin SB . (1999). Nat. Genet., 21, 103–107.

  • Chen S, Supakar PC, Vellanoweth RL, Song CS, Chatterjee B and Roy AK . (1997). Mol. Endocrinol., 11, 3–15.

  • Chomczynski P and Sacchi N . (1987). Anal. Biochem., 162, 156–159.

  • Culig Z, Hoffmann J, Erdel M, Eder IE, Hobisch A, Hittmair A, Bartsch G, Utermann G, Schneider MR, Parczyk K and Klocker H . (1999). Br. J. Cancer, 81, 242–251.

  • Culig Z, Klocker H, Bartsch G and Hobisch A . (2002). Endocr. Relat. Cancer, 9, 155–170.

  • de Vere White R, Meyers F, Chi SG, Chamberlain S, Siders D, Lee F, Stewart S and Gumerlock PH . (1997). Eur. Urol., 31, 1–6.

  • Debes J and Tindall D . (2002). Cancer Lett., 187, 1.

  • Doetzlhofer A, Rotheneder H, Lagger G, Koranda M, Kurtev V, Brosch G, Wintersberger E and Seiser C . (1999). Mol. Cell. Biol., 19, 5504–5511.

  • Eder IE, Culig Z, Ramoner R, Thurnher M, Putz T, Nessler-Menardi C, Tiefenthaler M, Bartsch G and Klocker H . (2000). Cancer Gene Ther., 7, 997–1007.

  • Faber PW, van Rooij HC, van der Korput HA, Baarends WM, Brinkmann AO, Grootegoed JA and Trapman J . (1991). J. Biol. Chem., 266, 10743–10749.

  • Ferrari AC, Chachoua A, Singh H, Rosenthal M, Taneja S, Bednar M, Mandeli J and Muggia F . (2001). Cancer, 91, 2039–2045.

  • Gao M, Ossowski L and Ferrari AC . (1999). J. Cell. Physiol., 179, 336–346.

  • Geck P, Maffini MV, Szelei J, Sonnenschein C and Soto AM . (2000). Proc. Natl. Acad. Sci. USA, 97, 10185–10190.

  • Gregory CW, Hamil KG, Kim D, Hall SH, Pretlow TG, Mohler JL and French FS . (1998). Cancer Res., 58, 5718–5724.

  • Grossmann ME, Huang H and Tindall DJ . (2001). J. Natl. Cancer Inst., 93, 1687–1697.

  • Grossmann ME and Tindall DJ . (1995). J. Biol. Chem., 270, 10968–10975.

  • Hobisch A, Culig Z, Radmayr C, Bartsch G, Klocker H and Hittmair A . (1995). Cancer Res., 55, 3068–3072.

  • Isaacs JT and Coffey DS . (1981). Cancer Res., 41, 5070–5075.

  • Kumar MV, Jones EA, Grossmann ME, Blexrud MD and Tindall DJ . (1994). Nucleic Acids Res., 22, 3693–3698.

  • Kumar VL, Majumder PK and Kumar V . (2002). Asian J. Androl., 4, 229–231.

  • Latil A, Bieche I, Vidaud D, Lidereau R, Berthon P, Cussenot O and Vidaud M . (2001). Cancer Res., 61, 1919–1926.

  • Leo ME, Bilhartz DL, Bergstralh EJ and Oesterling JE . (1991). J. Urol., 145, 802–806.

  • Linja MJ, Savinainen KJ, Saramaki OR, Tammela TL, Vessella RL and Visakorpi T . (2001). Cancer Res., 61, 3550–3555.

  • Loidl P . (1994). Chromosoma, 103, 441–449.

  • McPhaul MJ . (2002). Recent Prog. Horm. Res., 57, 181–194.

  • Mizokami A and Chang C . (1994). J. Biol. Chem., 269, 25655–25659.

  • Partin AW, Carter HB, Chan DW, Epstein JI, Oesterling JE, Rock RC, Weber JP and Walsh PC . (1990). J. Urol., 143, 747–752.

  • Petros JA and Andriole GL . (1993). Urol. Clin. North Am., 20, 749–756.

  • Riegman PH, Vlietstra RJ, van der Korput JA, Romijn JC and Trapman J . (1989). Biochem. Biophys. Res. Commun., 159, 95–102.

  • Ruizeveld de Winter JA . (1994). J. Histochem. Cytochem., 42, 125–126.

  • Ruizeveld de Winter JA, Janssen PJ, Sleddens HM, Verleun-Mooijman MC, Trapman J, Brinkmann AO, Santerse AB, Schroder FH and van der Kwast TH . (1994). Am. J. Pathol., 144, 735–746.

  • Song CS, Jung MH, Supakar PC, Chatterjee B and Roy AK . (1999). Mol. Endocrinol., 13, 1487–1496.

  • Sowa Y, Orita T, Minamikawa S, Nakano K, Mizuno T, Nomura H and Sakai T . (1997). Biochem. Biophys. Res. Commun., 241, 142–150.

  • Supakar PC, Jung MH, Song CS, Chatterjee B and Roy AK . (1995). J. Biol. Chem., 270, 837–842.

  • Supakar PC, Song CS, Jung MH, Slomczynska MA, Kim JM, Vellanoweth RL, Chatterjee B and Roy AK . (1993). J. Biol. Chem., 268, 26400–26408.

  • Takane KK and McPhaul MJ . (1996). Mol. Cell. Endocrinol., 119, 83–93.

  • Taplin ME, Bubley GJ, Shuster TD, Frantz ME, Spooner AE, Ogata GK, Keer HN and Balk SP . (1995). N. Engl. J. Med., 332, 1393–1398.

  • Turner BM . (1998). Cell Mol. Life Sci., 54, 21–31.

  • Wang LG, Liu XM, Kreis W and Budman DR . (1997). Cancer Res., 57, 714–719.

  • Wang LG, Liu XM, Li ZR, Denstman S and Bloch A . (1994). Cell Growth Differ., 5, 1243–1251.

  • Wang LG, Ossowski L and Ferrari AC . (2001). Cancer Res., 61, 7544–7551.

  • Yang TH, Tsai WH, Lee YM, Lei HY, Lai MY, Chen DS, Yeh NH and Lee SC . (1994). Mol. Cell. Biol., 14, 6068–6074.

  • Zegarra-Moro OL, Schmidt LJ, Huang H and Tindall DJ . (2002). Cancer Res., 62, 1008–1013.

  • Zhou J, Scholes J and Hsieh JT . (2001). Cancer Metastasis Rev., 20, 351–362.

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Acknowledgements

We are grateful to Xiaomei Liu for performing some of the EMSA experiments and to Dr Rafael Mira y Lopez, Mount Sinai School of Medicine, NY, for critical reading of the manuscript. This work was supported by the TJ Martell Foundation for Cancer Leukemia and AIDS Research, The Chemotherapy Foundation, the USPHS Research Grant CA9813501 (ACF and LGF), and USPHS Research Grant CA-40758 and Samuel Waxman Cancer Research Foundation (LO).

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  1. Department of Medicine, Division of Hematology/Oncology, Mount Sinai School of Medicine, Box 1129, 1 Gustave Levy Place, New York, 10029, NY, USA

    Long G Wang, Liliana Ossowski & Anna C Ferrari

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  1. Long G Wang
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  2. Liliana Ossowski
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  3. Anna C Ferrari
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Correspondence to Anna C Ferrari.

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Wang, L., Ossowski, L. & Ferrari, A. Androgen receptor level controlled by a suppressor complex lost in an androgen-independent prostate cancer cell line. Oncogene 23, 5175–5184 (2004). https://doi.org/10.1038/sj.onc.1207654

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