Role of the Polycomb Repressive Complex 2 in Acute Promyelocytic Leukemia

Epigenetic changes are common alterations in cancer cells. Here, we have investigated 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-RARα fusion protein. We show...

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Bibliographic Details
Published in:Cancer cell 2007-06, Vol.11 (6), p.513-525
Main Authors: Villa, Raffaella, Pasini, Diego, Gutierrez, Arantxa, Morey, Lluis, Occhionorelli, Manuela, Viré, Emmanuelle, Nomdedeu, Josep F., Jenuwein, Thomas, Pelicci, Pier Giuseppe, Minucci, Saverio, Fuks, Francois, Helin, Kristian, Di Croce, Luciano
Format: Article
Language:English
Subjects:
Carrier Proteins - physiology
Cell Differentiation
CELLCYCLE
DNA
DNA Methylation
Epigenesis, Genetic
Gene Silencing
Granulocytes - physiology
Histones
Humans
Leukemia, Promyelocytic, Acute - metabolism
Nuclear Proteins - physiology
Oncogene Proteins, Fusion - genetics
Oncogene Proteins, Fusion - physiology
Polycomb Repressive Complex 2
Polycomb-Group Proteins
Repressor Proteins - metabolism
Tretinoin - pharmacology
Tumor Cells, Cultured
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Summary:Epigenetic changes are common alterations in cancer cells. Here, we have investigated 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-RARα fusion protein. We 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 demethylation of PML-RARα target genes. This results in promoter reactivation and granulocytic differentiation. Importantly, the epigenetic alterations caused by PML-RARα can be reverted by retinoic acid treatment of primary blasts from leukemic patients. Our results demonstrate that the direct targeting of Polycomb group proteins by an oncogene plays a key role during carcinogenesis.
ISSN:1535-6108
1878-3686
DOI:10.1016/j.ccr.2007.04.009