Prostate cancer is the most prevalent male malignancy with just under one million new cases worldwide each year [
1]. Treatment pathways for this disease are relatively well defined and include surgery, radiotherapy and/or hormonal therapy. While the majority of patients with early stage disease are cured, 10-15% patient still develop locally recurrent or metastatic disease and have a significantly reduced survival rate [
2]. Despite the general adoption of docetaxel chemotherapy agents and novel agents such as abiraterone [
3], there is still an urgent need to develop effective new treatments, and therefore it is necessary to explore new target proteins and intracellular signalling pathways.
Recently, considerable interest has been shown in genes that play key roles in defining the identity of cells and tissues in early development and which therefore also have important regulatory roles in cell proliferation and survival. One group of genes that fit into this category are the
HOX family of transcription factors [
4]. HOX proteins are characterised in part by a highly conserved homeodomain that mediates DNA binding, together with a defined set of co-factors that modify their function including members of PBX family [
5‐
7]. The pro-proliferative and anti-apoptotic roles of some
HOX genes in development make them potential oncogenes, and indeed there are numerous reports of
HOX overexpression in a range of malignancies, including prostate cancer [
4,
8‐
11]. Although definitive oncogenic roles for some
HOX genes have been described, in general studies on the function of individual
HOX genes in cancer have been complicated by the high levels of sequence identity and functional redundancy exhibited by most members [
12,
13]. This functional redundancy in particular has made the results of conventional knock-down studies (using for example siRNA) hard to interpret. As an alternative approach we developed a peptide, HXR9 that acts as a competitive antagonist of the interaction between HOX proteins and their PBX co-factor. This interaction is mediated by a conserved hexapeptide sequence shared by the majority of HOX proteins, and HXR9 can globally repress HOX function through mimicking this peptide [
14‐
22]. In this study we show that prostate tumours have a highly dysregulated pattern of
HOX expression and that HXR9 induces apoptosis in prostate cancer derived cell lines through a mechanism that involves a rapid increase in expression of the
cFos gene. Furthermore, HXR9 can block prostate tumour growth
in vivo for an extended period, suggesting that HXR9 or its derivatives might represent a possible therapeutic option for locally recurrent prostate cancer.