Methyltransferase Recruitment and DNA Hypermethylation of Target Promoters by an Oncogenic Transcription Factor
Luciano Di Croce,1*
Veronica A. Raker,1
Massimo Corsaro,1
Francesco Fazi,2
Mirco Fanelli,15
Mario Faretta,1
Francois Fuks,4
Francesco Lo Coco,3
Tony Kouzarides,4
Clara Nervi,2
Saverio Minucci,1
Pier Giuseppe Pelicci16*
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.
1 Department of Experimental Oncology, European
Institute of Oncology, Milan, Italy.
2 Department of
Histology and Medical Embryology,
3 Department of
Cellular Biotechnology and Hematology, University of Rome, "La
Sapienza," Rome, Italy.
4 Wellcome/CRC Institute
and Department of Pathology, Cambridge University, Cambridge, UK.
5 Department of Morphological Science, University of
Camerino, Italy.
6 Italian Foundation for Cancer
Research (FIRC) Institute for Molecular Oncology, Milan, Italy.
*
To whom correspondence should be addressed. E-mail:
ldicroce{at}lar.ieo.it (L.D.C.); pgpelicci{at}ieo.it (P.G.P.)
