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


METHODS
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).


CONCLUSIONS
This study suggests that folate supplementation could be a promising adjuvant for the future design of antiglioma therapies in preclinical and/or clinical studies.
Hervouet
Eric
E
Institut National de la Sante et de la Recherche Medicale U892, Centre de Recherche en Cancérologie, Equipe Apoptose et Progression Tumorale, Nantes, France.
Debien
Emilie
E
Campion
Loic
L
Charbord
Jeremie
J
Menanteau
Jean
J
Vallette
Francois M
FM
Cartron
Pierre-Francois
PF
D000368:Aged; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D000077214:Becaplermin; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology; D019587:Dietary Supplements; D005492:Folic Acid / Q000008:administration & dosage*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010982:Platelet-Derived Growth Factor / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D020574:Proto-Oncogene Proteins c-sis; D012091:Repetitive Sequences, Nucleic Acid / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051705:Sp3 Transcription Factor / Q000378:metabolism; D016019:Survival Analysis; D000077022:Survivin; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics; D000097584:DNA Methyltransferase 3B
D051017:Apoptosis Regulatory Proteins; D000077214:Becaplermin; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D015254:DNA Modification Methylases; D045643:DNA Repair Enzymes; D003606:Dacarbazine; D005492:Folic Acid; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D010982:Platelet-Derived Growth Factor; D020574:Proto-Oncogene Proteins c-sis; D016329:Sp1 Transcription Factor; D051705:Sp3 Transcription Factor; D000077022:Survivin; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins; D000097584:DNA Methyltransferase 3B; C491073:BCL2L2 protein, human; C107489:BIRC5 protein, human; C000717967:DNMT3A protein, human; C515491:MGMT protein, human