EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization.
The ecotropic viral integration site-1 (EVI-1) is a nuclear transcription factor and has an essential function in the proliferation/maintenance of haematopoietic stem cells. Aberrant expression of EVI-1 has been frequently found in myeloid leukaemia as well as in several solid tumours, and is associated with a poor patient survival. It was recently shown that EVI-1 associates with two different histone methyltransferases (HMTs), SUV39H1 and G9a. However, the functional roles of these HMTs in EVI-1-mediated leukemogenesis remain unclear. In this study, we showed that EVI-1 physically interacts with SUV39H1 and G9a, but not with Set9. Immunofluorescence analysis revealed that EVI-1 colocalizes with these HMTs in nuclei. We also found that the catalytically inactive form of SUV39H1 abrogates the transcriptional repression mediated by EVI-1, suggesting that SUV39H1 is actively involved in EVI-1-mediated transcriptional repression. Furthermore, RNAi-based knockdown of SUV39H1 or G9a in Evi-1-expressing progenitors significantly reduced their colony-forming activity. In contrast, knockdown of these HMTs did not impair bone marrow immortalization by E2A/HLF. These results indicate that EVI-1 forms higher-order complexes with HMTs, and this association has a role in the transcription repression and bone marrow immortalization. Targeting these HMTs may be of therapeutic benefit in the treatment for EVI-1-related haematological malignancies.
Goyama
S
S
Department of Hematology and Oncology, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo 113-8655, Japan.
Nitta
E
E
Yoshino
T
T
Kako
S
S
Watanabe-Okochi
N
N
Shimabe
M
M
Imai
Y
Y
Takahashi
K
K
Kurokawa
M
M
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism*; D019556:COS Cells; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000032:analysis / Q000502:physiology*; D006649:Histocompatibility Antigens / Q000032:analysis / Q000502:physiology*; D011495:Histone-Lysine N-Methyltransferase / Q000032:analysis / Q000502:physiology*; D006801:Humans; D000074008:MDS1 and EVI1 Complex Locus Protein; D008745:Methylation; D008780:Methyltransferases / Q000032:analysis / Q000502:physiology*; D011519:Proto-Oncogenes / Q000502:physiology*; D012097:Repressor Proteins / Q000032:analysis / Q000502:physiology*; D014157:Transcription Factors / Q000032:analysis / Q000502:physiology*
D004268:DNA-Binding Proteins; D006649:Histocompatibility Antigens; D000074008:MDS1 and EVI1 Complex Locus Protein; C063575:MECOM protein, human; D012097:Repressor Proteins; D014157:Transcription Factors; C407843:SUV39H1 protein, human; D008780:Methyltransferases; C445405:EHMT2 protein, human; D011495:Histone-Lysine N-Methyltransferase