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Loss of HOXC6 expression induces apoptosis in prostate cancer cells


We have performed whole genome expression profiling of 28 patient prostate tumor samples and 12 normal prostate samples and identified 55 upregulated and 60 downregulated genes significantly changed in prostate tumor samples compared to normal prostate tissues. Among the members of the upregulated gene set was the developmental transcription factor Homeobox C6 (HOXC6). Silencing of HOXC6 expression using small-interfering RNA (siRNA) resulted in decreased proliferation rates for both androgen-dependent LnCaP cells and the LnCaP-derived androgen-independent C4-2 cell line. Flow cytometry and immunoblotting for the caspase-cleaved form of poly-ADP ribose polymerase (PARP) determined that the decrease in cell numbers was due to increased apoptosis. To validate the specificity of the siRNA-induced apoptosis, LnCaP cells were cotransfected with siRNA specific to the HOXC6 3′UTR and a mammalian expression vector containing the HOXC6 open reading frame, but lacking the 3′UTR. Overexpression of HOXC6 rescued the LnCaP cells from HOXC6 siRNA-induced apoptosis, and increased growth of control GFP siRNA-transfected cells. Expression profiling of HOXC6 siRNA transfections and HOXC6 overexpression identified neutral endopeptidase (NEP) and insulin-like growth factor binding protein-3 (IGFBP-3) as potential proapoptotic repression targets of HOXC6. Our data suggest that HOXC6 may be a novel potential therapeutic target for prostate cancer.

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  • Abate-Shen C . (2002). Nat. Rev. Cancer, 2, 777–785.

  • Abdulkadir SA, Magee JA, Peters TJ, Kaleem Z, Naughton CK, Humphrey PA and Milbrandt J . (2002). Mol. Cell. Biol., 22, 1495–1503.

  • Aberdam D, Negreanu V, Sachs L and Blatt C . (1991). Mol. Cell. Biol., 11, 554–557.

    Article  CAS  Google Scholar 

  • ACS (2003). American Cancer Society.

  • Bodey B, Bodey Jr B, Groger AM, Siegel SE and Kaiser HE . (2000a). Anticancer Res., 20, 2711–2716.

  • Bodey B, Bodey Jr B, Siegel SE and Kaiser HE . (2000b). Anticancer Res., 20, 1769–1780.

  • Bodey B, Bodey Jr B, Siegel SE and Kaiser HE . (2000c). Anticancer Res., 20, 3281–3286.

  • Bodey B, Bodey Jr B, Siegel SE, Luck JV and Kaiser HE . (2000d). Anticancer Res., 20, 2717–2721.

  • Bolstad BM, Irizarry RA, Astrand M and Speed TP . (2003). Bioinformatics, 19, 185–193.

    Article  CAS  Google Scholar 

  • Bowen C, Bubendorf L, Voeller HJ, Slack R, Willi N, Sauter G, Gasser TC, Koivisto P, Lack EE, Kononen J, Kallioniemi OP and Gelmann EP . (2000). Cancer Res., 60, 6111–6115.

  • Braasch DA and Corey DR . (2002). Biochemistry, 41, 4503–4510.

    Article  CAS  Google Scholar 

  • Castronovo V, Kusaka M, Chariot A, Gielen J and Sobel M . (1994). Biochem. Pharmacol., 47, 137–143.

  • Chariot A, Castronovo V, Le P, Gillet C, Sobel ME and Gielen J . (1996). Biochem. J., 319 (Part 1), 91–97.

    Article  CAS  Google Scholar 

  • Chen H, Nandi AK, Li X and Bieberich CJ . (2002). Cancer Res., 62, 338–340.

  • Cheng WS, Giandomenico V, Pastan I and Essand M . (2003). Endocrinology, 144, 3433–3440.

    Article  CAS  Google Scholar 

  • Cillo C . (1994). Invasion Metast., 14, 38–49.

  • DeYoung MP, Tress M and Narayanan R . (2003). Proc. Natl. Acad. Sci. USA, 100, 4760–4765.

  • Dhanasekaran SM, Barrette TR, Ghosh D, Shah R, Varambally S, Kurachi K, Pienta KJ, Rubin MA and Chinnaiyan AM . (2001). Nature, 412, 822–826.

    Article  CAS  Google Scholar 

  • Elbashir SM, Harborth J, Lendeckel W, Yalcin A, Weber K and Tuschl T . (2001). Nature, 411, 494–498.

    Article  CAS  Google Scholar 

  • Ernst T, Hergenhahn M, Kenzelmann M, Cohen CD, Bonrouhi M, Weninger A, Klaren R, Grone EF, Wiesel M, Gudemann C, Kuster J, Schott W, Staehler G, Kretzler M, Hollstein M and Grone HJ . (2002). Am. J. Pathol., 160, 2169–2180.

  • Essand M, Vasmatzis G, Brinkmann U, Duray P, Lee B and Pastan I . (1999). Proc. Natl. Acad. Sci. USA, 96, 9287–9292.

  • Fanayan S, Firth SM, Butt AJ and Baxter RC . (2000). J. Biol. Chem., 275, 39146–39151.

    Article  CAS  Google Scholar 

  • Felsher DW . (2003). Nat. Rev. Cancer, 3, 375–380.

  • Firth SM and Baxter RC . (2002). Endocrinol. Rev., 23, 824–854.

  • Garcia-Gasca A and Spyropoulos DD . (2000). Dev. Dyn., 219, 261–276.

    Article  Google Scholar 

  • Grimberg A, Liu B, Bannerman P, El-Deiry WS and Cohen P . (2002). Int. J. Oncol., 21, 327–335.

  • Hu G, Lee H, Price SM, Shen MM and Abate-Shen C . (2001). Development, 128, 2373–2384.

  • Jones FS, Holst BD, Minowa O, De Robertis EM and Edelman GM . (1993). Proc. Natl. Acad. Sci. USA, 90, 6557–6561.

  • Kawabe T, Muslin AJ and Korsmeyer SJ . (1997). Nature, 385, 454–458.

    Article  CAS  Google Scholar 

  • Kim MJ, Bhatia-Gaur R, Banach-Petrosky WA, Desai N, Wang Y, Hayward SW, Cunha GR, Cardiff RD, Shen MM and Abate-Shen C . (2002a). Cancer Res., 62, 2999–3004.

  • Kim MJ, Cardiff RD, Desai N, Banach-Petrosky WA, Parsons R, Shen MM and Abate-Shen C . (2002b). Proc. Natl. Acad. Sci. USA, 99, 2884–2889.

  • Krishnan AV, Peehl DM and Feldman D . (2003). J. Cell. Biochem., 88, 363–371.

  • Lewis EB . (1978). Nature, 276, 565–570.

    Article  CAS  Google Scholar 

  • Loy CJ, Sim KS and Yong EL . (2003). Proc. Natl. Acad. Sci. USA, 100, 4562–4567.

  • Luo L, Yang X, Takihara Y, Knoetgen H and Kessel M . (2004). Nature, 427, 749–753.

    Article  CAS  Google Scholar 

  • Magee JA, Abdulkadir SA and Milbrandt J . (2003). Cancer Cell, 3, 273–283.

    Article  CAS  Google Scholar 

  • Maulbecker CC and Gruss P . (1993). Cell Growth Differ., 4, 431–441.

  • Miller GJ, Miller HL, van Bokhoven A, Lambert JR, Werahera PN, Schirripa O, Lucia MS and Nordeen SK . (2003). Cancer Res., 63, 5879–5888.

  • Moreno CS, Park S, Nelson K, Ashby D, Hubalek F, Lane WS and Pallas DC . (2000). J. Biol. Chem., 275, 5257–5263.

    Article  CAS  Google Scholar 

  • Nakamura T, Largaespada DA, Lee MP, Johnson LA, Ohyashiki K, Toyama K, Chen SJ, Willman CL, Chen IM, Feinberg AP, Jenkins NA, Copeland NG and Shaughnessy Jr JD . (1996). Nat. Genet., 12, 154–158.

  • Rajah R, Valentinis B and Cohen P . (1997). J. Biol. Chem., 272, 12181–12188.

    Article  CAS  Google Scholar 

  • Shen R, Sumitomo M, Dai J, Hardy DO, Navarro D, Usmani B, Papandreou CN, Hersh LB, Shipp MA, Freedman LP and Nanus DM . (2000). Mol. Cell Endocrinol., 170, 131–142.

  • Stein S, Fritsch R, Lemaire L and Kessel M . (1996). Mech. Dev., 55, 91–108.

  • Sumitomo M, Milowsky MI, Shen R, Navarro D, Dai J, Asano T, Hayakawa M and Nanus DM . (2001). Cancer Res., 61, 3294–3298.

  • Sumitomo M, Shen R, Goldberg JS, Dai J, Navarro D and Nanus DM . (2000). Cancer Res., 60, 6590–6596.

  • Thelen P, Burfeind P, Grzmil M, Voigt S, Ringert RH and Hemmerlein B . (2004). Int. J. Oncol., 24, 1085–1092.

  • Tusher VG, Tibshirani R and Chu G . (2001). Proc. Natl. Acad. Sci. USA, 98, 5116–5121.

  • Velasco-Miguel S, Buckbinder L, Jean P, Gelbert L, Talbott R, Laidlaw J, Seizinger B and Kley N . (1999). Oncogene, 18, 127–137.

    Article  CAS  Google Scholar 

  • Wei H and Pallas DC . (2003) unpublished data.

  • Wolfgang CD, Essand M, Lee B and Pastan I . (2001). Cancer Res., 61, 8122–8126.

  • Wolfgang CD, Essand M, Vincent JJ, Lee B and Pastan I . (2000). Proc. Natl. Acad. Sci. USA, 97, 9437–9442.

  • Xia X, Cheng A, Akinmade D and Hamburger AW . (2003). Mol. Cell. Biol., 23, 1717–1725.

  • Yoshinouchi M, Yamada T, Kizaki M, Fen J, Koseki T, Ikeda Y, Nishihara T and Yamato K . (2003). Mol. Ther., 8, 762–768.

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We thank Dr Alain Chariot for the generous gift of clones of human HOXC6-1 and HOXC6-2, Dr Leland Chung for the generous gift of the LnCaP, C4-2, DU145, and PC3 cell lines, and Drs Jeremy Boss for use of the Bio-Rad I-cycler and Paul Wade for critical reading of the manuscript and helpful discussions. This research was supported in part by NIH Grant K22-CA96560 to CSM and the Department of Pathology & Laboratory Medicine, Emory University School of Medicine. This work is the subject of a US provisional patent application. The publication costs of this article were defrayed in part by payment of page charges. This article must therefore be hereby marked ‘advertisement’ in accordance with 18 USC section 1734 solely to indicate this fact.

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Correspondence to Carlos S Moreno.

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Ramachandran, S., Liu, P., Young, A. et al. Loss of HOXC6 expression induces apoptosis in prostate cancer cells. Oncogene 24, 188–198 (2005).

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  • prostate cancer
  • HOXC6
  • microarray
  • siRNA
  • apoptosis
  • IGFBP-3
  • NEP

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