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Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142 [S. K. D., H-y. Y., R. A. W.]; Department of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts 02114 [S. K. D.]; Harvard Medical School, Boston, Massachusetts 02115 [S. K. D.]; Children’s Medical Research Institute, Westmead, N.S.W. 2145, Australia [R. R. R.]; and Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands [R. L. B.]
The acquisition of expression of hTERT, the catalytic subunit of the telomerase enzyme, seems to be an essential step in the development of a majority of human tumors. However, little is known about the mechanisms preventing telomerase gene expression in normal and transformed cells that do not express hTERT. Using a methylation-specific PCR-based assay, we have found that the CpG island associated with the hTERT gene is unmethylated in telomerase-negative primary tissues and nonimmortalized cultured cells, indicating that mechanisms independent of DNA methylation are sufficient to prevent hTERT expression. The hTERT CpG island is methylated in many telomerase-negative and telomerase-positive cultured cells and tumors, but the extent of methylation did not correlate with expression of hTERT. Demethylation of DNA with 5-azacytidine in two cell lines induced expression of hTERT, suggesting that DNA methylation can contribute to hTERT repression in some cells. Together, these data show that the hTERT CpG island can undergo cytosine methylation in cultured cells and tumors and that DNA methylation may contribute to the regulation of the hTERT gene, but that CpG island methylation is not responsible for repressing hTERT expression in most telomerase-negative cells.
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