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′-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′ 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.
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References
Akiyama Y, Maesawa C, Ogasawara S, Terashima M, Masuda T . (2003). Cell-type-specific repression of the maspin gene is disrupted frequently by demethylation at the promoter region in gastric intestinal metaplasia and cancer cells. Am J Pathol 163: 1911–1919.
Bender TP, Kremer CS, Kraus M, Buch T, Rajewsky K . (2004). Critical functions for c-Myb at three checkpoints during thymocyte development. Nat Immunol 5: 721–729.
Black AR, Jensen D, Lin SY, Azizkhan JC . (1999). Growth cell cycle regulation of Sp1 phosphorylation. J Biol Chem 274: 1207–1215.
Bright RK, Vocke CD, Emmert-Buck MR, Duray PH, Solomon D, Fetsch P et al. (1997). Generation and genetic characterization of immortal human prostate epithelial cell lines derived from primary cancer specimens. Cancer Res 57: 995–1002.
Brothman AR, Swanson G, Maxwell TM, Cui J, Murphy KJ, Herrick J et al. (2005). Global hypomethylation is common in prostate cancer cells: a quantitative predictor for clinical outcome? Cancer Genet Cytogenet 156: 31–36.
Cho M, Uemura H, Kim SC, Kawada Y, Yoshida K, Hirao Y et al. (2001). Hypomethylation of the MN/CA9 promoter and upregulated MN/CA9 expression in human renal cell carcinoma. Br J Cancer 85: 563–567.
Esteller M, Corn PG, Baylin SB, Herman JG . (2001). A gene hypermethylation profile of human cancer. Cancer Res 61: 3225–3229.
Frampton J, Ramqvist T, Graf T . (1996). v-Myb of E26 leukemia virus up-regulates bcl-2 and suppresses apoptosis in myeloid cells. Genes Dev 10: 2720–2721.
Gaubatz S, Imhof A, Dosch R, Werner O, Mitchell P, Buettner R et al. (1995). Transcriptional activation by Myc is under negative control by the transcription factor AP-2. EMBO J 14: 1508–1519.
Gaudet F, Hodgson JG, Eden A, Jackson-Grusby L, Dausman J, Gray JW et al. (2003). Induction of tumors in mice by genomic hypomethylation. Science 300: 489–492.
Gibadulinova A, Barathova M, Kopacek J, Hulikova A, Pastorekova S, Kettmann R et al. (2005). Expression of S100P protein correlates with and contributes to the tumorigenic capacity of HeLa cervical carcinoma cells. Oncol Rep 14: 575–582.
Gupta A, Godwin AK, Vanderveer L, Lu A, Liu J . (2003). Hypomethylation of the synuclein gamma gene CpG island promotes its aberrant expression in breast carcinoma and ovarian carcinoma. Cancer Res 63: 664–673.
Herman J, Graff J, Myohanen S, Nelkin B, Baylin S . (1996). Methylation – specific PCR: a novel PCR assay for methylation status of CpG islands (DNA methylation/tumor suppressor gene/p16/p15). Proc Natl Acad Sci USA 93: 9821–9826.
Huang S, Jean D, Luca M, Tainsky MA, Bar-Eli M . (1998). Loss of AP-2 results in downregulation of c-KIT and enhancement of melanoma tumorigenicity and metastasis. EMBO J 17: 4358–4369.
Iozzo RV, Eichstetter I, Danielson KG . (1995). Aberrant expression of the growth factor Wnt-5A in human malignancy. Cancer Res 55: 3495–3499.
Ishii Y, Kasukabe T, Honma Y . (2005). Immediate up-regulation of the calcium-binding protein S100P and its involvement in the cytokinin-induced differentiation of human myeloid leukemia cells. Biochim Biophys Acta 1745: 156–165.
Jemal A, Tiwari RC, Murray T, Ghafoor A Samuels A, Ward E et al. (2005). Cancer statistics, 2005. CA Cancer J Clin 55: 10–30.
Jiang MS, Tang QQ, McLenithan J, Geiman D, Shillinglaw W, Henzel WJ et al. (1998). Derepression of the C/EBPalpha gene during adipogenesis: identification of AP-2alpha as a repressor. Proc Natl Acad Sci USA 95: 3467–3471.
Jones PA, Laird PW . (1999). Cancer epigenetics comes of age. Nat Genet 21: 163–167.
Jurata LW, Kenny DA, Gill GN . (1996). Nuclear LIM interactor, a rhombotin and LIM homeodomain interacting protein, is expressed early in neuronal development. Proc Natl Acad Sci USA 93: 11693–11698.
Klempnauer KH . (1993). Methylation-sensitive DNA binding by v-myb and c-myb proteins. Oncogene 8: 111–115.
Lang G, White JR, Argent-Katwala MJ, Allinson CG, Weston K . (2005). Myb proteins regulate the expression of diverse target genes. Oncogene 24: 1375–1384.
Levenson CW, Shay NF, Lee-Ambrose LM, Cousins RJ . (1993). Regulation of cysteine-rich intestinal protein by dexamethasone in the neonatal rat. Proc Natl Acad Sci USA 90: 712–715.
Li LC, Okino ST, Dahiya R . (2004). DNA methylation in prostate cancer. Biochim Biophys Acta 1704: 87–102.
Liang H, Chen Q, Coles AH, Anderson SJ, Pihan G, Bradley A et al. (2003). Wnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue. Cancer Cell 4: 349–360.
Mackay A, Jones C, Dexter T, Silva RL, Bulmer K, Jones A et al. (2003). cDNA microarray analysis of genes associated with ERBB2 (HER2/neu) overexpression in human mammary luminal epithelial cells. Oncogene 22: 2680–2688.
Matei D, Graeber TG, Baldwin RL, Karlan BY, Rao J, Chang DD . (2002). Gene expression in epithelial ovarian carcinoma. Oncogene 21: 6289–6298.
McPherson LA, Baichwal VR, Weigel RJ . (1997). Identification of ERF-1 as a member of the AP2 transcription factor family. Proc Natl Acad Sci USA 94: 4342–4347.
Miller JR, Hocking AM, Brown JD, Moon RT . (1999). Mechanism and function of signal transduction by the Wnt/beta-catenin and Wnt/Ca2+ pathways. Oncogene 18: 7860–7872.
Mousses S, Bubendorf L, Wagner U, Hostetter G, Kononen J, Cornelison R et al. (2002). Clinical validation of candidate genes associated with prostate cancer progression in the CWR22 model system using tissue microarrays. Curr Opin Chem Biol 6: 97–101.
Mucenski M, McLain K, Kier AB, Swerdlow SH, Schreiner CM, Miller TA et al. (1991). A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis. Cell 65: 677–689.
Ogishima T, Shiina H, Breault JE, Tabatabai L, Bassett WW, Enokida H et al. (2005). Increased heparanase expression is caused by promoter hypomethylation and up-regulation of transcriptional factor early growth response-1 in human prostate cancer. Clin Cancer Res 11: 1028–1036.
Ording E, Bergholtz S, Brendeford EM, Jamin N, Gabrielsen OS . (1996). Flexibility in the second half-site sequence recognised by the c-Myb R2 domain – in vitro and in vivo analysis. Oncogene 13: 1043–1051.
Oshimo Y, Nakayama H, Ito R, Kitadai Y, Yoshida K, Chayama K et al. (2003). Promoter methylation of cyclin D2 gene in gastric carcinoma. Int J Oncol 23: 1663–1670.
Pukrop T, Klemm F, Hagemann T, Gradl D, Schulz M, Siemes S et al. (2006). Wnt 5a signaling is critical for macrophage-induced invasion of breast cancer cell lines. PNAS 103: 5454–5459.
Sato N, Fukushima N, Matsubayashi H, Goggins M . (2004). Identification of maspin and S100P as novel hypomethylation targets in pancreatic cancer using global gene expression profiling. Oncogene 23: 1531–1538.
Sato N, Maitra A, Fukushima N, van Heek NT, Matsubayashi H, Iacobuzio-Donahue CA et al. (2003). Frequent hypomethylation of multiple genes overexpressed in pancreatic ductal adenocarcinoma. Cancer Res 63: 4158–4166.
Tokizane T, Shiina H, Igawa M, Enokida H, Urakami S, Kawakami T et al. (2005). Cytochrome P450 1B1 is overexpressed and regulated by hypomethylation in prostate cancer. Clin Cancer Res 11: 5793–5801.
Wang D, Shin TH, Kudlow JE . (1997). Transcription factor AP-2 controls transcription of the human transforming growth factor-alpha gene. J Biol Chem 272: 14244–14250.
Zeng YX, Somasundaram K, Deiry WS . (1997). AP2 inhibits cancer cell growth and activates p21WAF1/CIP1 expression. Nat Genet 15: 78–82.
Zhu WG, Srinivasan K, Dai Z, Duan W, Druhan LJ, Ding H et al. (2003). Methylation of adjacent CpG sites affects Sp1/Sp3 binding and activity in the p21(Cip1) promoter. Mol Cell Biol 23: 4056–4065.
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This research was supported by the NCRI Prostate Cancer Initiative, MRC Grant GO100116.
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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).
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Wang, Q., Williamson, M., Bott, S. et al. Hypomethylation of WNT5A, CRIP1 and S100P in prostate cancer. Oncogene 26, 6560–6565 (2007). https://doi.org/10.1038/sj.onc.1210472
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DOI: https://doi.org/10.1038/sj.onc.1210472
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