Abnormal regulation of DNA methyltransferase expression during colorectal carcinogenesis

Somatic changes in CpG dinucleotide methylation occur quite commonly in hum an cancer cell DNA. Relative to DNA from normal human colonic cells, DNA fr om human colorectal cancer cells typically displays regional CpG dinucleoti de hypermethylation amid global CpG dinucleotide hypomethylation. The role of the maintenance DNA methyltransferase (DNMT1) in the acquisition of such abnormal CpG dinucleotide methylation changes in colorectal cancer cells r emains controversial; in one study, 60-200-fold increases in DNMT1 mRNA exp ression were detected in colorectal polyps and cancers relative to normal c olonic tissue [W. S. El-Deiry et al., Proc. Natl, Acad, Sci, USA, 88: 3470- 3474, 1991], whereas in another study, only small increases in DNMT1 mRNA e xpression, commensurate with differences in cell proliferation accompanying colonic tumorigenesis, were observed [P. J. Lee et al., Proc. Natl, Acad, Sci, USA, 93: 10366-10370, 1996]. To definitively ascertain whether abnorma l DNMT1 expression might accompany human colorectal carcinogenesis, we subj ected a series of normal and neoplastic colonic tissues to immunohistochemi cal staining using a polyclonal antiserum raised against a DNMT1 polypeptid e. A concordance of DNMT1 expression with the expression of PCNA and other cell proliferation markers, such as Ki-67 and DNA topoisomerase II alpha, w as observed in normal colonic epithelial cells and in cells comprising othe r normal epithelia and lymphoid tissues. The polypeptide p21, which has bee n reported to undermine DNMT1 binding to proliferating cell nuclear antigen at DNA replication sites, was not expressed by normal colonic cells contai ning DNMT1 and other cell proliferation markers. In adenomatous polyps, alt hough DNMT1 expression coincided with the expression of other cell prolifer ation markers, many DNMT1-expressing cells also expressed p21. The fidelity of DNMT1 expression was further undermined in colorectal carcinomas, in wh ich a striking heterogeneity in DNMT1 expression, with some carcinoma cells containing very high DNMT1 levels and others containing very Low DNMT1 lev els, was observed. These results indicate that human colorectal carcinogene sis is accompanied by a progressive dysregulation of DNMT1 expression and s uggest that abnormalities in DNMT1 expression may contribute to the abnorma l CpG dinucleotide methylation changes characteristic of human colorectal c arcinoma cell DNA.