In silico mining identifies IGFBP3 as a novel target of methylation in prostate cancer

Abstract

Promoter hypermethylation is central in deregulating gene expression in cancer. Identification of novel methylation targets in specific cancers provides a basis for their use as biomarkers of disease occurrence and progression. We developed an in silico strategy to globally identify potential targets of promoter hypermethylation in prostate cancer by screening for 5 0 CpG islands in 631 genes that were reported as downregulated in prostate cancer. A virtual archive of 338 potential targets of methylation was produced. One candidate, IGFBP3, was selected for investigation, along with glutathione-S-transferase pi (GSTP1), a well-known methylation target in prostate cancer. Methylation of IGFBP3 was detected by quantitative methylation-specific PCR in 49/79 primary prostate adenocarcinoma and 7/14 adjacent preinvasive high-grade prostatic intraepithelial neoplasia, but in only 5/37 benign prostatic hyperplasia (Po0.0001) and in 0/39 histologically normal adjacent prostate tissue, which implies that methylation of IGFBP3 may be involved in the early stages of prostate cancer development. Hypermethylation of IGFBP3 was only detected in samples that also demonstrated methylation of GSTP1 and was also correlated with Gleason score X7 (P ¼ 0.01), indicating that it has potential as a prognostic marker. In addition, pharmacological demethylation induced strong expression of IGFBP3 in LNCaP prostate cancer cells. Our concept of a methylation candidate gene bank was successful in identifying a novel target of frequent hypermethylation in earlystage prostate cancer. Evaluation of further relevant genes could contribute towards a methylation signature of this disease.

IGFBP-3 hypermethylation-derived deficiency mediates cisplatin resistance in non-small-cell lung cancer

“…In addition, in a p53 and/or IGF-I-independent pathway, methylation could also be the mechanism responsible for inhibiting the apoptosis mediated by IGFBP-3 through the activation of the TGF-b receptor TbR-V, (Rajah et al, 1997;Huang and Huang, 2005). IGFBP-3-methylation has been correlated with clinicopathological features indicative of poor prognosis in prostate and ovarian cancers (Wiley et al, 2006;Perry et al, 2007) and in the early stages of NSCLC patients (Chang et al, 2002a(Chang et al, , 2002b, likely indicating that those patients have intrinsic resistance to CDDP. However, we know that those patients with unmethylated IGFBP-3 in early stages could also progress towards a methylated promoter after CDDP treatment, thus showing acquired resistance.…”

Epigenetic regulation of insulin-like growth factor binding protein-3 (IGFBP-3) in cancer

“…One target IGFBP-3 was found to be methylated in 49/79 primary prostate adenocarcinoma samples, and in 7/14 adjacent pre-invasive high-grade prostatic intraepithelial neoplasia (PIN). However, it was only observed in 5/37 benign prostatic hyperplasia and in 0/39 histologically normal adjacent prostate tissue (Perry et al 2007). …”

The emergence of DNA methylation as a key modulator of aberrant cell death in prostate cancer

“…Development of an apoptotic methylation signature, consisting of a panel of genes, whose aberrant expression is important for prostate cancer development and progression, may also prove beneficial as a tumour biomarker in prostate cancer. Recently we have undertaken a combined bioinformatics and wet-lab approach, to identify novel apoptotic gene targets for methylation in prostate cancer (Murphy et al Abstract: DMMC International Workshop-Epigenetics:From Mechanisms to medicine;25-26 June 2007, Dublin); an approach we have used previously to identify novel targets of hypermethylation such as IGFBP3 (Perry et al 2007b). Such research is in its infancy, but with further identification of markers and standardization of techniques, it may be possible to significantly increase the sensitivity of detecting low volume disease (Perry et al 2006).…”

“…The most significant gene that has been described is GSTP1, which has been found to be methylated in O90% of prostate cancers (Lin et al 2001, Maruyama et al 2002. In our own lab, we have focused on the insulin-like growth factor (IGF) pathway and have recently identified IGFPB3 as a novel target of methylation in prostate cancer (Perry et al 2007b). …”