Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor.
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.
Di Croce
Luciano
L
Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. ldicroce@lar.ieo.it
Raker
Veronica A
VA
Corsaro
Massimo
M
Fazi
Francesco
F
Fanelli
Mirco
M
Faretta
Mario
M
Fuks
Francois
F
Lo Coco
Francesco
F
Kouzarides
Tony
T
Nervi
Clara
C
Minucci
Saverio
S
Pelicci
Pier Giuseppe
PG
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
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