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J. Biol. Chem., Vol. 278, Issue 17, 15333-15340, April 25, 2003
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From the Department of Biological Chemistry, The Johns Hopkins
University School of Medicine, Baltimore, Maryland 21205-2185
One of the "signature" phenotypes of highly
malignant, poorly differentiated tumors, including hepatomas, is their
remarkable propensity to utilize glucose at a much higher rate than
normal cells, a property frequently dependent on the marked
overexpression of type II hexokinase (HKII). As the expression of the
gene for this enzyme is nearly silent in liver tissue, we tested the
possibility that DNA methylation/demethylation events may be involved
in its regulation. Initial studies employing methylation restriction endonuclease analysis provided evidence for differential methylation patterns for the HKII gene in normal hepatocytes and hepatoma cells,
the latter represented by a highly glycolytic model cell line (AS-30D).
Subsequently, sequencing following sodium bisulfite treatment revealed
18 methylated CpG sites within a CpG island (
Glucose Metabolism in Cancer
EVIDENCE THAT DEMETHYLATION EVENTS PLAY A ROLE IN ACTIVATING
TYPE II HEXOKINASE GENE EXPRESSION*
, and
350 to +781 bp) in the
hepatocyte gene but none in that of the hepatoma. In addition,
treatment of a hepatocyte cell line with the DNA methyltransferase
inhibitors, 5'-azacytidine and 5'-aza-2'-deoxycytidine, activated basal
expression levels of HKII mRNA and protein. Finally, stably
transfecting the hepatocyte cell line with DNA demethylase also
resulted in activating the basal expression levels of HKII mRNA and
protein. These novel observations indicate that one of the initial
events in activating the HKII gene during either transformation or
tumor progression may reside at the epigenetic level.
*
This work was supported in part by National Institutes of
Health Grant CA 80118 (to P. L. P.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Supported as a research fellow by National Institutes of Health
Grant T32 CA 67751. Present address: Dept. of Neurological Surgery,
Wayne State University School of Medicine, Detroit, MI 48201.
§
To whom correspondence should be addressed. Tel.: 410-955-3827;Fax:
410-614-1944; E-mail: ppederse@jhmi.edu.
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