124 The galectin-3 gene Z-VAD-FMK order (LGALS3), a member of the galectin family, has recently been found to be hypermethylated in prostate adenocarcinoma.126�C128 Galectins, a family of ��-galactoside-binding lectins, are multifunctional proteins involved in a variety of biological processes such as growth development, immune functions, apoptosis, and cancer metastasis.129�C131 Our studies and those of others indicate that galectins are transcriptionally regulated by DNA methylation.126,132 Gal3 was found strongly expressed in normal, BPH, and high grade PIN (HGPIN) tissues, whereas expression of gal3 was found decreased in prostate adenocarcinoma.127,133,134 By bisulfite sequencing of multiple prostate cancer specimens, the gal3 promoter of stage II tumors was seen to be heavily methylated throughout its entire length, but the gal3 promoter of stage III and IV tumors was lightly methylated.
Whereas gal3 promoter in stage III showed few methylation sites, mostly between ?199 to ?252 nt, the gal3 promoter from stage IV tumor specimens was methylated between ?112 to ?227 nt. In stage I prostate cancer, however, both light and heavy methylation is evident in the gal3 promoter. In multiple normal prostate and BPH samples, the gal3 promoter was almost unmethylated. Overall, results indicated that the decreased expression of gal3 in tumor prostate is associated with the hypermethylation of its promoter. Methylated Genes Suitable for Early Detection of Prostate Cancer Although many genes are observed to be methylated in prostate cancer, a few genes have been investigated as targets for early detection (Table 2).
Most have insufficient methylation frequency to provide the needed sensitivity, while other methylated genes are also present in the BPH, making them non-specific. The most suitable gene appears to be GSTP1, which is also the best studied in this regard. GSTP1 promoter hypermethylation constitutes an ideal DNA-based biomarker for prostate cancer because it is present in up to 90% of prostatic cancer tissues and in 2/3 of high grade prostatic intraepithelial neoplasia (HGPIN) but not or rarely present in BPH tissue.17,135�C138 Other genes are also used in combination with GSTP1 in multiple-gene cohort assays. Using ejaculates, Suh et al first reported the presence of methylated GSTP1 in 4 out of 9 patients with prostate cancer.
139 Later, Goessl et al found methylation in the GSTP1 promoter Anacetrapib in 72% (23/32) of sera, in 50% (4/8) of ejaculates, and in 36% (4/11) of urine samples from patients with prostate cancer, but none in any body fluid from 26 control patients with BPH.140 A qMSP (quantitative methylation specific PCR) study by Jeronimo et al reported the highest sensitivity (90.9%) and specificity (100%).52 By measuring the relative level of methylated GSTP1 DNA to MYOD1 (i.e.