title: Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor.
abstract: DNA methylation of tumor suppressor genes is a frequent mechanism of transcriptional silencing in cancer. The molecular mechanisms underlying the specificity of methylation are unknown. We report here that the leukemia-promoting PML-RAR fusion protein induces gene hypermethylation and silencing by recruiting DNA methyltransferases to target promoters and that hypermethylation contributes to its leukemogenic potential. Retinoic acid treatment induces promoter demethylation, gene reexpression, and reversion of the transformed phenotype. These results establish a mechanistic link between genetic and epigenetic changes during transformation and suggest that hypermethylation contributes to the early steps of carcinogenesis.
authors.affiliation: Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. ldicroce@lar.ieo.it
authors.forename: Luciano
authors.initials: L
authors.lastname: Di Croce
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Raker
authors.forename: Massimo
authors.initials: M
authors.lastname: Corsaro
authors.forename: Francesco
authors.initials: F
authors.lastname: Fazi
authors.forename: Mirco
authors.initials: M
authors.lastname: Fanelli
authors.forename: Mario
authors.initials: M
authors.lastname: Faretta
authors.forename: Francois
authors.initials: F
authors.lastname: Fuks
authors.forename: Francesco
authors.initials: F
authors.lastname: Lo Coco
authors.forename: Tony
authors.initials: T
authors.lastname: Kouzarides
authors.forename: Clara
authors.initials: C
authors.lastname: Nervi
authors.forename: Saverio
authors.initials: S
authors.lastname: Minucci
authors.forename: Pier Giuseppe
authors.initials: PG
authors.lastname: Pelicci
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D001665:Binding Sites; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D002471:Cell Transformation, Neoplastic; D003001:Cloning, Molecular; D018899:CpG Islands; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D000077209:Decitabine; D005091:Exons; D015870:Gene Expression; D020868:Gene Silencing; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics; D009154:Mutation; D009363:Neoplasm Proteins / Q000378:metabolism*; D015514:Oncogene Proteins, Fusion / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015032:Zinc / Q000494:pharmacology
chemical_list: C000717967:DNMT3A protein, human; D009363:Neoplasm Proteins; D015514:Oncogene Proteins, Fusion; D018168:Receptors, Retinoic Acid; D011993:Recombinant Fusion Proteins; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; C082925:retinoic acid receptor beta; D014212:Tretinoin; D000077209:Decitabine; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A; D006655:Histone Deacetylases; D015032:Zinc; D001374:Azacitidine