Folate supplementation limits the aggressiveness of glioma via the remethylation of DNA repeats element and genes governing apoptosis and proliferation

Clin Cancer Res. 2009 May 15;15(10):3519-29. doi: 10.1158/1078-0432.CCR-08-2062.

Abstract

Purpose: We have investigated whether the folate supplementation could be used to limit the aggressiveness of glioma through the DNA remethylation because (a) the cancer genome is characterized by a low level of DNA methylation (or 5-methylcytosine, 5 mC); and (b) folate is the main generator of S-adenosyl-methionine, the methyl donor molecule in the DNA methylation reaction catalyzed by the DNA methyltranferases.

Experimental design: The effects of folate supplementations were analyzed on the global DNA methylation status, the methylation status of DNA repeat element, the sensitivity of temozolomide-induced apoptosis, and the proliferation index of glioma cells. Finally, we analyzed whether the DNA methylation level could be used as a prognostic factor and/or a biomarker in an antiglioma therapy using folate supplementation as an adjuvant.

Results: Our data show that gliomagenesis is accompanied by a reduction in 5 mC levels and that this low level of 5 mC is a poor prognostic factor in Glioblastoma Multiforme patients. We also show that folate supplementation enhanced the DNA remethylation through the Sp1/Sp3-mediated transcriptional up-regulation of genes coding for Dnmt3a and Dnmt3b proteins, two de novo methyltranferases. Finally, we show that the folate-induced DNA methylation limits proliferation and increases the sensitivity to temozolomide-induced apoptosis in glioma cells through methylation of the genes implicated in these processes (PDGF-B, MGMT, survivin, and bcl-w).

Conclusion: This study suggests that folate supplementation could be a promising adjuvant for the future design of antiglioma therapies in preclinical and/or clinical studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Apoptosis / drug effects
  • Apoptosis / genetics
  • Apoptosis Regulatory Proteins / genetics*
  • Becaplermin
  • Cell Line, Tumor
  • Cell Proliferation*
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA Methylation*
  • DNA Modification Methylases / genetics
  • DNA Repair Enzymes / genetics
  • Dacarbazine / analogs & derivatives
  • Dacarbazine / pharmacology
  • Dietary Supplements
  • Folic Acid / administration & dosage*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioma / drug therapy
  • Glioma / genetics*
  • Glioma / pathology
  • Humans
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins / genetics
  • Middle Aged
  • Neoplasm Invasiveness
  • Platelet-Derived Growth Factor / genetics
  • Protein Binding / drug effects
  • Proto-Oncogene Proteins c-sis
  • Repetitive Sequences, Nucleic Acid / genetics
  • Sp1 Transcription Factor / metabolism
  • Sp3 Transcription Factor / metabolism
  • Survival Analysis
  • Survivin
  • Temozolomide
  • Tumor Suppressor Proteins / genetics

Substances

  • Apoptosis Regulatory Proteins
  • BCL2L2 protein, human
  • BIRC5 protein, human
  • Inhibitor of Apoptosis Proteins
  • Microtubule-Associated Proteins
  • Platelet-Derived Growth Factor
  • Proto-Oncogene Proteins c-sis
  • Sp1 Transcription Factor
  • Survivin
  • Tumor Suppressor Proteins
  • Sp3 Transcription Factor
  • Becaplermin
  • Dacarbazine
  • Folic Acid
  • DNA Modification Methylases
  • DNA (Cytosine-5-)-Methyltransferases
  • DNA methyltransferase 3A
  • DNA methyltransferase 3B
  • MGMT protein, human
  • DNA Repair Enzymes
  • Temozolomide