GSTP1 CpG island DNA hypermethylation in hepatocellular carcinomas INTERNATIONAL JOURNAL OF ONCOLOGY Tchou, J. C., Lin, X. H., Freije, D., Isaacs, W. B., Brooks, J. D., Rashid, A., De Marzo, A. M., Kanai, Y., Hirohashi, S., Nelson, W. G. 2000; 16 (4): 663-676


Glutathione S-transferases, enzymes that defend cells against damage mediated by oxidant and electrophilic carcinogens, may be critical determinants of cancer pathogenesis. We report here that the pathogenesis of hepatocellular carcinoma (HCC), one of the most common cancers in the world, frequently involves an accumulation of somatic DNA methylation changes at GSTP1, the gene encoding the pi-class glutathione S-transferase. For our study, Hep3B HCC cells and a cohort of 20 HCC tissue specimens were subjected to analysis for GSTP1 expression and for somatic GSTP1 alterations. GSTP1 DNA hypermethylation in HCC DNA was assessed by Southern blot analysis, via a polymerase chain reaction (PCR) assay, and by using a genomic sequencing approach. Hep3B HCC cells failed to express GSTP1 mRNA or GSTP1 polypeptides. Similarly, HCC cells in 19 of 20 HCC cases were devoid of GSTP1 polypeptides. By Southern blot analysis, DNA from Hep3B HCC cells displayed abnormal GSTP1 hypermethylation. Treatment of Hep3B HCC cells in vitro with the DNA methyltransferase inhibitor 5-aza-deoxycytidine both reversed GSTP1 DNA hypermethylation and restored GSTP1 expression. Using a PCR assay, somatic GSTP1 DNA hypermethylation was also detected in HCC DNA from 17 of 20 HCC cases. Genomic sequencing analyses, undertaken to map 5-methyldeoxycytidine nucleotides located at the GSTP1 transcriptional regulatory region, frequently detected somatic DNA hypermethylation near the gene promoter in HCC DNA. The data indicate that GSTP1 DNA hypermethylation changes appear frequently in human HCC. In addition, the data raise the possibility that somatic GSTP1 inactivation, via hypermethylation, may contribute to the pathogenesis of HCC.

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