title: Regulation of expression of O6-methylguanine-DNA methyltransferase and the treatment of glioblastoma (Review).
abstract: O-6-methylguanine-DNA methyltransferase (MGMT) is an abundantly expressed nuclear protein dealkylating O6-methylguanine (O6-MG) DNA residue, thus correcting the mismatches of O6-MG with a thymine residue during DNA replication. The dealkylating effect of MGMT is relevant not only in repairing DNA mismatches produced by environmental alkylating agents promoting tumor pathogenesis, but also when alkylating molecules are applied in the chemotherapy of different cancers, including glioma, the most common primary tumor of the central nervous system. Elevated MGMT gene expression is known to confer resistance to the treatment with the alkylating drug temozolomide in patients affected by gliomas and, on the contrary, methylation of MGMT gene promoter, which causes reduction of MGMT protein expression, is known to predict a favourable response to temozolomide. Thus, detecting expression levels of MGMT gene is crucial to indicate the option of alkylating agents or to select patients directly for a second line targeted therapy. Further study is required to gain insights into MGMT expression regulation, that has attracted growing interest recently in MGMT promoter methylation, histone acetylation and microRNAs expression. The review will focus on the epigenetic regulation of MGMT gene, with translational applications to the identification of biomarkers predicting response to therapy and prognosis.
authors.affiliation: Department of Pathology and Diagnostics, University Hospital, Verona, Italy.
authors.forename: Giulio
authors.initials: G
authors.lastname: Cabrini
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Enrica
authors.initials: E
authors.lastname: Fabbri
authors.affiliation: Department of Oncology, S. Croce and Carle Teaching Hospital, Cuneo, Italy.
authors.forename: Cristiana
authors.initials: C
authors.lastname: Lo Nigro
authors.affiliation: Department of Pathology and Diagnostics, University Hospital, Verona, Italy.
authors.forename: Maria Cristina
authors.initials: MC
authors.lastname: Dechecchi
authors.affiliation: Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Gambari
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D015254:DNA Modification Methylases / Q000235:genetics* / Q000378:metabolism*; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism*; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D019008:Drug Resistance, Neoplasm; D044127:Epigenesis, Genetic; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011401:Promoter Regions, Genetic / Q000187:drug effects; D000077204:Temozolomide; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D025521:Tumor Suppressor Proteins; D003606:Dacarbazine; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D045643:DNA Repair Enzymes; D000077204:Temozolomide