GSTP1 CpG island hypermethylation is responsible for the absence of GSTP1 expression in human prostate cancer cells

Xiaohui Lin, Metin Tascilar, Wen Hsiang Lee, Wouter J. Vles, Byron H. Lee, Ravi Veeraswamy, Kekule Asgari, Diha Freije, Bastian Van Rees, Wesley R. Gage, G. Steven Bova, William B. Isaacs, James D. Brooks, Theodore L. Deweese, Angelo M. De Marzo, William G. Nelson

Research output: Contribution to journalArticle

190 Scopus citations

Abstract

GSTP1 CpG island hypermethylation is the most common somatic genome alteration described for human prostate cancer (PCA); lack of GSTP1 expression is characteristic of human PCA cells in vivo. We report here that loss of GSTP1 function may have been selected during the pathogenesis of human PCA. Using a variety of techniques to detect GSTP1 CpG island DNA hypermethylation in PCA DNA, we found only hypermethylated GSTP1 alleles in each PCA cell in all but two PCA cases studied. In these two cases, CpG island hypermethylation was present at only one of two GSTP1 alleles in PCA DNA. In one of the cases, DNA hypermethylation at one GSTP1 allele and deletion of the other GSTP1 allele were evident. In the other case, an unmethylated GSTP1 allele was detected, accompanied by abundant GSTP1 expression. GSTP1 CpG island DNA hypermethylation was responsible for lack of GSTP1 expression by LNCaP PCA cells: Treatment of the cells with 5-azacytidine (5-aza-C), an inhibitor of DNA methyltransferases, reversed the GSTP1 promoter DNA hypermethylation, activated GSTP1 transcription, and restored GSTP1 expression. GSTP1 promoter activity, assessed via transfection of GSTP1 promoter-CAT reporter constructs in LNCaP cells, was inhibited by SssI-catalyzed CpG dinucleotide methylation. Remarkably, although selection for loss of GSTP1 function may be inferred for human PCA, GSTP1 did not act like a tumor suppressor gene, as LNCaP cells expressing GSTP1, either after 5-aza-C treatment or as a consequence of transfection with GSTP1 cDNA, grew well in vitro and in vivo. Perhaps, GSTP1 inactivation may render prostatic cells susceptible to additional genome alterations, caused by electrophilic or oxidant carcinogens, that provide a selective growth advantage. All rights reserved

Original languageEnglish (US)
Pages (from-to)1815-1826
Number of pages12
JournalAmerican Journal of Pathology
Volume159
Issue number5
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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    Lin, X., Tascilar, M., Lee, W. H., Vles, W. J., Lee, B. H., Veeraswamy, R., Asgari, K., Freije, D., Van Rees, B., Gage, W. R., Bova, G. S., Isaacs, W. B., Brooks, J. D., Deweese, T. L., De Marzo, A. M., & Nelson, W. G. (2001). GSTP1 CpG island hypermethylation is responsible for the absence of GSTP1 expression in human prostate cancer cells. American Journal of Pathology, 159(5), 1815-1826. https://doi.org/10.1016/S0002-9440(10)63028-3