Promoter methylation in prostate cancer and its application for the early detection of prostate cancer using serum and urine samples

Abstract

Prostate cancer is the second most common cancer and the second leading cause of cancer death in men. However, prostate cancer can be effectively treated and cured, if it is diagnosed in its early stages when the tumor is still confined to the prostate. Combined with the digital rectal examination, the PSA test has been widely used to detect prostate cancer. But, the PSA screening method for early detection of prostate cancer is not reliable due to the high prevalence of false positive and false negative results. Epigenetic alterations including hypermethylation of gene promoters are believed to be the early events in neoplastic progression and thus these methylated genes can serve as biomarkers for the detection of cancer from clinical specimens. This review discusses DNA methylation of several gene promoters during prostate carcinogenesis and evaluates the usefulness of monitoring methylated DNA sequences, such as GSTP1, RASSF1A, RARβ2 and galectin-3, for early detection of prostate cancer in tissue biopsies, serum and urine.

Keywords: DNA methylation; GSTP1; early detection; gal3; prostate cancer.

Figure 1

DNA methylation catalyzed by DNA methyltransferase. DNA methyltransferase transfers methyl group from S-adenosyl methionine (SAM-CH₃) to cytosine yielding S-adenosyl homocysteine (SAH) and 5-methylcytosine.

Figure 2

Simplified cartoon showing gene transcription by unmethylated promoter (A) and gene silencing by the methylated promoter (B). A) In normal prostate and pituitary tissues, tumor suppressor promoter is unmethylated and accessible to binding to the transcription factors such as AP-1 and Sp-1 for stimulation of gal3 transcription. B) In prostate cancer, promoters of several genes such as tumor suppressor, DNA repair gene, and gal3 are methylated and therefore bound by the methyl binding proteins (MBD) and histone deacetylase (HDAC). Thus the methylated promoter is not accessible to binding to the transcription factors and inactive.

Figure 3

Schematic representation of MS-PCR. In normal and BPH prostate tissues, the gal3 promoter is unmethylated, whereas in stage I and II, it is methylated heavily. However, gal3 promoter is lightly methylated in stage III and IV. Stage-specific cytosine methylation of the gal3 promoter enabled the development of MS-PCR for the detection of stage I and II PCa.