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Methyltransferase Recruitment and DNA Hypermethylation of Target Promoters by an Oncogenic Transcription Factor
Luciano Di Croce,1*Veronica A. Raker,1Massimo Corsaro,1Francesco Fazi,2Mirco Fanelli,15Mario Faretta,1Francois Fuks,4Francesco Lo Coco,3Tony Kouzarides,4Clara Nervi,2Saverio Minucci,1Pier Giuseppe Pelicci16*
DNA methylation of tumor suppressor genes is a frequent
mechanism of transcriptional silencing in cancer. The molecular
mechanismsunderlying the specificity of methylation are unknown. We
reporthere that the leukemia-promoting PML-RAR fusion protein inducesgene hypermethylation and silencing by recruiting DNA
methyltransferasesto target promoters and that hypermethylation
contributes to itsleukemogenic potential. Retinoic acid treatment
induces promoterdemethylation, gene reexpression, and reversion of the
transformedphenotype. These results establish a mechanistic link
betweengenetic and epigenetic changes during transformation and
suggestthat 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.)
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J. L. Grisolano, J. O'Neal, J. Cain, and M. H. Tomasson (2003)
PNAS
100, 9506-9511
|Abstract »|Full Text »|PDF »
Frequent Hypomethylation of Multiple Genes Overexpressed in Pancreatic Ductal Adenocarcinoma.
N. Sato, A. Maitra, N. Fukushima, N. T. van Heek, H. Matsubayashi, C. A. Iacobuzio-Donahue, C. Rosty, and M. Goggins (2003)
Cancer Res.
63, 4158-4166
|Abstract »|Full Text »|PDF »
Cooperation of Cytokine Signaling with Chimeric Transcription Factors in Leukemogenesis: PML-Retinoic Acid Receptor Alpha Blocks Growth Factor-Mediated Differentiation.
V. T. Phan, D. B. Shultz, B.-T. H. Truong, T. J. Blake, A. L. Brown, T. J. Gonda, M. M. Le Beau, and S. C. Kogan (2003)
Mol. Cell. Biol.
23, 4573-4585
|Abstract »|Full Text »|PDF »
Genomic targets of the human c-Myc protein.
P. C. Fernandez, S. R. Frank, L. Wang, M. Schroeder, S. Liu, J. Greene, A. Cocito, and B. Amati (2003)
Genes & Dev.
17, 1115-1129
|Abstract »|Full Text »|PDF »
