Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer

Abstract

Oligoarray analysis of a matched pair of prostate cancer and normal cell lines derived from the same radical prostatectomy specimen identified 113 candidate hypomethylated genes that were overexpressed in the cancer cells and contained CpG islands. Hypomethylation of wingless-related MMTV integration site 5A (WNT5A), S100 calcium-binding protein P (S100P) and cysteine-rich protein 1(CRIP1) was confirmed in the cancer cells by bisulfite sequencing. Treatment of the corresponding normal prostate epithelial cells 1542-NPTX with the DNA methyltransferase inhibitor 5-Aza-2 0 -deoxycytidine (5-aza-CdR) induced higher levels of mRNA expression and partial loss of methylation on these genes. Primary prostate cancers were tested using methylation-specific polymerase chain reaction. WNT5A was hypomethylated in 11/17 (65%) tumors, S100P in 8/16 (50%) and CRIP1 in 13/20 (65%). Bisulfite sequencing of a section of the 5 0 untranslated region (UTR) of WNT5A revealed that three CpG sites (15, 24 and 35) were consistently methylated (93%) in the normal cell line and normal tissues, but not in the prostate cancer cell line and eight primary prostate cancers. Multiple putative binding sites for the transcription factors SP1 and AP-2 were found adjacent to CpG sites 15 and 24. A putative c-Myb binding site was located within the CpG site 35. Anti-c-Myb antibody co-precipitation with WNT5A was methylation-sensitive in 1542-NPTX cells. It is likely that an epigenetic mechanism regulates WNT5A expression in prostate cancer.

Wnt5a signaling is involved in the aggressiveness of prostate cancer and expression of metalloproteinase

“…It has been shown that Wnt5a is upregulated at the transcriptional level in PCa by hypomethylation in the 5 0 -untranslated region and that three CpG sites were consistently methylated in normal tissues but not in primary PCa (Wang et al, 2007). It was also reported that membrane type 1-MMP is upregulated in PCa species and that membrane type 1-MMP-induced phenotypic changes are dependent on the expression of Wnt5a (Cao et al, 2008).…”

Targeting S100P Inhibits Colon Cancer Growth and Metastasis by Lentivirus-Mediated RNA Interference and Proteomic Analysis

“…Overexpression of S100P was observed in various cancers, including pancreatic (5), breast (6), colon (7), prostate (8) and lung carcinomas (9). S100P was also reported to correlate with tumor growth and metastasis in breast (6,10,11), colon (12) and pancreatic (3) cancer.…”

Gene expression profiling of the androgen independent prostate cancer cells demonstrates complex mechanisms mediating resistance to docetaxel

“…Normalization of androgen independent prostate tumors and is also associated with anti-apoptotic function of WNT5A. [27][28][29] A critical importance of calcium influx inhibition in reversing the docetaxel and multi-drug resistant phenotype was recently demonstrated in human lung cancer cell lines. 30 Taken together, our efforts to identify specific genes and molecular cascades mediating resistance to docetaxel in prostate cancer cells have yielded a narrow set of genes and associated specific cellular processes that appear highly relevant.…”