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Open Access Research article

Targeting HOX transcription factors in prostate cancer

Richard Morgan1*, Angie Boxall1, Kevin J Harrington2, Guy R Simpson1, Agnieszka Michael1 and Hardev S Pandha1

Author Affiliations

1 Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK

2 Targeted Therapy Team, Chester Beatty Laboratories, The Institute of Cancer Research, London, UK

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BMC Urology 2014, 14:17  doi:10.1186/1471-2490-14-17

Published: 5 February 2014

Abstract

Background

The HOX genes are a family of transcription factors that help to determine cell and tissue identity during early development, and which are also over-expressed in a number of malignancies where they have been shown to promote cell proliferation and survival. The purpose of this study was to evaluate the expression of HOX genes in prostate cancer and to establish whether prostate cancer cells are sensitive to killing by HXR9, an inhibitor of HOX function.

Methods

HOX function was inhibited using the HXR9 peptide. HOX gene expression was assessed by RNA extraction from cells or tissues followed by quantitative PCR, and siRNA was used to block the expression of the HOX target gene, cFos. In vivo modelling involved a mouse flank tumour induced by inoculation with LNCaP cells.

Results

In this study we show that the expression of HOX genes in prostate tumours is greatly increased with respect to normal prostate tissue. Targeting the interaction between HOX proteins and their PBX cofactor induces apoptosis in the prostate cancer derived cell lines PC3, DU145 and LNCaP, through a mechanism that involves a rapid increase in the expression of cFos, an oncogenic transcription factor. Furthermore, disrupting HOX/PBX binding using the HXR9 antagonist blocks the growth of LNCaP tumours in a xenograft model over an extended period.

Conclusion

Many HOX genes are highly over-expressed in prostate cancer, and prostate cancer cells are sensitive to killing by HXR9 both in vitro and in vivo. The HOX genes are therefore a potential therapeutic target in prostate cancer.

Keywords:
Prostate cancer; HXR9; HOX; PBX