MYC stimulates EZH2 expression by repression of its negative regulator miR-26a.
The MYC oncogene, which is commonly mutated/amplified in tumors, represents an important regulator of cell growth because of its ability to induce both proliferation and apoptosis. Recent evidence links MYC to altered miRNA expression, thereby suggesting that MYC-regulated miRNAs might contribute to tumorigenesis. To further analyze the impact of MYC-regulated miRNAs, we investigated a murine lymphoma model harboring the MYC transgene in a Tet-off system to control its expression. Microarray-based miRNA expression profiling revealed both known and novel MYC targets. Among the miRNAs repressed by MYC, we identified the potential tumor suppressor miR-26a, which possessed the ability to attenuate proliferation in MYC-dependent cells. Interestingly, miR-26a was also found to be deregulated in primary human Burkitt lymphoma samples, thereby probably being of clinical relevance. Although today only few miRNA targets have been identified in human disease, we could show that ectopic expression of miR-26a influenced cell cycle progression by targeting the bona fide oncogene EZH2, a Polycomb protein and global regulator of gene expression yet unknown to be regulated by miRNAs. Thus, in addition to directly targeting protein-coding genes, MYC modulates genes important to oncogenesis via deregulation of miRNAs, thereby vitally contributing to MYC-induced lymphomagenesis.
Sander
Sandrine
S
Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
Bullinger
Lars
L
Klapproth
Kay
K
Fiedler
Katja
K
Kestler
Hans A
HA
Barth
Thomas F E
TF
Möller
Peter
P
Stilgenbauer
Stephan
S
Pollack
Jonathan R
JR
Wirth
Thomas
T
D000818:Animals; D002051:Burkitt Lymphoma / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D004195:Disease Models, Animal; D000071221:Enhancer of Zeste Homolog 2 Protein; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D063151:Polycomb Repressive Complex 2; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000096:biosynthesis* / Q000235:genetics
D004268:DNA-Binding Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D011495:Histone-Lysine N-Methyltransferase; D035683:MicroRNAs; D063151:Polycomb Repressive Complex 2; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D012334:RNA, Neoplasm; D014157:Transcription Factors; C528163:MIRN26 microRNA, human; C498409:EZH2 protein, human; C498410:Ezh2 protein, mouse