DNA Methylation and the HOXC6 Paradox in Prostate Cancer

Abstract

Overexpression of the classical homeobox transcription factor HOXC6 is frequent in prostate cancers and correlates with adverse clinical parameters. Since surprisingly many HOXC6 target genes are downregulated in prostate cancer, it has been posited that oncogenic effects of HOXC6 in prostate cancer may be unmasked by concurrent epigenetic downregulation of target genes exerting tumor suppressive effects. To test this hypothesis, we have studied the expression of three HOXC6 target genes, CNTN1 (encoding a cell adhesion protein), DKK3 and WIF1 (encoding WNT growth factor antagonists) as well as DNA methylation of DKK3 and WIF1. HOXC6 upregulation and association with poor prognosis were confirmed in our tissue series. The three target genes were each significantly downregulated in cancer tissues and expression of each one correlated inversely with that of HOXC6. Cases with lower WIF1 expression showed significantly earlier recurrence (p = 0.021), whereas no statistical significance was reached for CNTN1 and DKK3. Hypermethylation of DKK3 or WIF1 gene promoters was observed in a subset of cancers with downregulated expression, but was often weak. Our data support the hypothesis that HOXC6 target genes exerting tumor-suppressive effects are epigenetically downregulated in prostate cancer, but DNA methylation appears to follow or bolster rather than to cause their transcriptional inactivation.

The role of HOXC6 in prostate cancer development

“…It was hypothesized that HOXC6 may activate tumor cell‐specific behaviors, such as increased cell proliferation, enhanced cell survival, changes in cell motility and invasion . We found that knockdown of HOXC6 expression resulted in a reduction of cell proliferation, both in androgen‐dependent and independent PCa cell lines, which is in agreement with some previous reports . As HOXC6 is a homeodomain‐containing transcription factor, the next step will be to study HOXC6 target genes.…”

“…In a previous study, it was shown that the HOXC6 upregulation was associated with poor prognosis . In contrast, we showed that HOXC6 protein expression in our radical prostatectomy series has no prognostic value.…”

HOXC6 in the prognosis of prostate cancer

“…In the present study, we measured the expression of HOXC6 in PCa tissues and cells. Also, the results showed that compared with normal controls, PCa tissues and cells manifested relatively heightened HOXC6 expression at mRNA and protein levels, which was in accordance with findings from previous reports [17,31]. Hence, HOXC6 might act as an oncogene in PCa.…”

HOXC6 gene silencing inhibits epithelial-mesenchymal transition and cell viability through the TGF-β/smad signaling pathway in cervical carcinoma cells

“…Supportively, evidence has demonstrated that HOXC6 gene has association with various tumor progressions. For instance, overexpressed HOXC6 is frequently observed in prostate cancers and relates to adverse clinical parameters [24]. Overexpressed HOXC6 is closely linked to poor survival of patients with gastric cancer, and contributes to gastric carcinogenesis progression [25].…”