Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor

Luciano Di Croce; Veronica A Raker; Massimo Corsaro; Francesco Fazi; Mirco Fanelli; Mario Faretta; Francois Fuks; Francesco Lo Coco; Tony Kouzarides; Clara Nervi; Saverio Minucci; Pier Giuseppe Pelicci

doi:10.1126/science.1065173

Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor

Science. 2002 Feb 8;295(5557):1079-82. doi: 10.1126/science.1065173.

Authors

Luciano Di Croce¹, Veronica A Raker, Massimo Corsaro, Francesco Fazi, Mirco Fanelli, Mario Faretta, Francois Fuks, Francesco Lo Coco, Tony Kouzarides, Clara Nervi, Saverio Minucci, Pier Giuseppe Pelicci

Affiliation

¹ Department of Experimental Oncology, European Institute of Oncology, Milan, Italy. [email protected]

PMID: 11834837
DOI: 10.1126/science.1065173

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Azacitidine / analogs & derivatives*
Azacitidine / pharmacology
Binding Sites
Cell Differentiation / drug effects
Cell Line
Cell Nucleus / metabolism
Cell Transformation, Neoplastic
Cloning, Molecular
CpG Islands
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases / metabolism*
DNA Methylation*
DNA Methyltransferase 3A
Decitabine
Exons
Gene Expression
Gene Silencing*
Histone Deacetylases / metabolism
Humans
Leukemia, Promyelocytic, Acute / genetics
Mutation
Neoplasm Proteins / metabolism*
Oncogene Proteins, Fusion / metabolism*
Promoter Regions, Genetic*
Receptors, Retinoic Acid / genetics*
Recombinant Fusion Proteins / metabolism
Transcription Factors / metabolism
Tretinoin / pharmacology
Tumor Cells, Cultured
Zinc / pharmacology

Substances

DNMT3A protein, human
Neoplasm Proteins
Oncogene Proteins, Fusion
Receptors, Retinoic Acid
Recombinant Fusion Proteins
Transcription Factors
promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein
retinoic acid receptor beta
Tretinoin
Decitabine
DNA (Cytosine-5-)-Methyltransferase 1
DNA (Cytosine-5-)-Methyltransferases
DNA Methyltransferase 3A
Histone Deacetylases
Zinc
Azacitidine