Polycomb and Cancer
Polycomb repressive complex 2 has been strongly implicated in cancer development, but to date mechanistic insight into the function of PRC2 in cancer cells is lacking. In addition, in mammalian cells, it is not well understood how PRC2 is targeted to promoter regions. Using as paradigm the oncogenic transcription factor PML-RAR, we are investigating the role of Polycomb group proteins in the establishment and maintenance of the aberrant silencing of tumor suppressor genes during transformation induced by the leukemia-associated PML-RAR fusion protein. Our initial results show that in leukemic cells knockdown of SUZ12, a key component of Polycomb repressive complex 2 (PRC2), reverts not only histone modification but also induces DNA de-methylation of PML-RAR target genes. This leads to promoter re-activation and granulocytic differentiation. Importantly, the epigenetic alterations caused by PML-RAR can be reverted by retinoic acid treatment of primary blasts from leukemic patients. Our data demonstrate that the direct targeting of Polycomb group proteins by an oncogene plays a key role during carcinogenesis.
Selected publications from our group on this research line:
- Villa R, Pasini D, Gutierrez A, Viré E, Nomdedeu JF, Jenuwein T, Pelicci PG, Minucci S, Fuks F, Helin K, and Di Croce L (2007) Role of the Polycomb repressive complex 2 in leukemia. Cancer Cell, 11, 513-525.
- Lee MG., Villa R., Trojer P., Norman J., Yan KP., Reinberg D., Di Croce L., Shiekhattar R. (2007) Demethylation of H3K27 regulates Polycomb recruitment and H2A ubiquitination. Science, 318, 447-450.
- Villa R., De Santis F., Raker V., Corsaro M., Gutierrez A., Buschbeck M., Morey L., Varas F., Bossi D., Minucci S., Pelicci PG. and Di Croce L. (2006) The methyl-CpG binding protein MBD1 is required for PML-RARα function. PNAS 103, 1400-1405.
- Di Croce, L., Raker V.A., Corsaro M., Fazi, F., Fanelli M., Fuks, F., Lo Coco, F., Kouzarides, T., Nervi, C., Minucci, S. and Pelicci, P.G. (2002) Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science 295, 1079-1082.