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-RARalpha 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-RARalpha target genes. This results in promoter reactivation and granulocytic differentiation. Importantly, the epigenetic alterations caused by PML-RARalpha 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.
Villa
Raffaella
R
Centre de Regulacio Genomica, c/ Dr. Aiguader 88, 08003 Barcelona, Spain.
Pasini
Diego
D
Gutierrez
Arantxa
A
Morey
Lluis
L
Occhionorelli
Manuela
M
Viré
Emmanuelle
E
Nomdedeu
Josep F
JF
Jenuwein
Thomas
T
Pelicci
Pier Giuseppe
PG
Minucci
Saverio
S
Fuks
Francois
F
Helin
Kristian
K
Di Croce
Luciano
L
D002352:Carrier Proteins / Q000502:physiology*; D002454:Cell Differentiation; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006098:Granulocytes / Q000502:physiology; D006657:Histones; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000378:metabolism*; D009363:Neoplasm Proteins; D009687:Nuclear Proteins / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000502:physiology*; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins / Q000378:metabolism*; D014157:Transcription Factors; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D002352:Carrier Proteins; D006657:Histones; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D063146:Polycomb-Group Proteins; D012097:Repressor Proteins; C430461:SUZ12 protein, human; D014157:Transcription Factors; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D014212:Tretinoin; D063151:Polycomb Repressive Complex 2