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Loss of HOXC6 expression induces apoptosis in prostate cancer cells

Abstract

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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Acknowledgements

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). https://doi.org/10.1038/sj.onc.1207906

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  • DOI: https://doi.org/10.1038/sj.onc.1207906

Keywords

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

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