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 owing to 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 in order 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 likely being of clinical relevance. While 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.

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Sander S, Bullinger L, Klapproth K, Fiedler K, Kestler HA, Barth TF, Möller P, Stilgenbauer S, Pollack JR, Wirth T