Repressing the repressor A new mode of MYC action in lymphomagenesis

The MYC oncogene is often mutated or amplified in human tumors resulting in increased activity of the transcription factor. Recent evidence suggested that MYC not only regulates expression of protein-coding genes directly, but also controls expression of miRNAs thereby using a second mode to impact on gene expression programs. The importance of miRNAs in MYC-driven tumorigenesis has been enlightened by studying cell line and murine lymphoma models with conditional expression of MYC. The application of microarray technology revealed both MYC-induced and MYC-repressed miRNAs. A miRNA consistently repressed by MYC in multiple tumors was miR-26a indicating that this miRNA might have strong tumor suppressor function for MYC-induced lymphomas. Indeed, ectopic miR-26a expression in MYC-dependent cells resulted in attenuated proliferation and impaired cell cycle progression. When the effector pathway for miR-26a was elucidated, the Polycomb complex protein EZH2, a global regulator of gene expression, was identified as a direct target. The suppression of miR-26a mediated attenuation of EZH2 expression by MYC was shown to play a critical role in lymphomagenesis. Thus, MYC-induced oncogenesis does not only depend on direct targeting of protein-coding genes, but also on modulating them via deregulation of their targeting miRNAs, thereby significantly impacting lymphomagenesis.