MicroRNAs As Key Downstream Effectors of MYC
Our interest in non-canonical functions of MYC was spurred by the early discovery that some of well-known MYC-repressed genes (e.g., the angiogenesis inhibitor thrombospondin-1) are regulated by MYC at the level of mRNA turnover, not promoter silencing. At the time, we didn’t know what the underlying mechanism was, but the discovery of the first MYC-activated microRNA cluster, miR-17-92 (a.k.a. oncomir-1) provided us with an intriguing clue. We indeed discovered that thrombospondin-1 is an essential target of the MYC - miR-17-92 axis, and that this targeting drives tumor angiogenesis.
This was the first demonstration of microRNAs affecting tumor microenvironment – and the second report of microRNAs playing a role in gene repression by MYC. Subsequently, we showed, in collaboration with the Mendell and Dang labs, that MYC also down-regulates select microRNA leading to a broad gene activation program. The mechanisms of microRNA deregulation by MYC range from promoter-based to biogenesis-mediated. For example, we found that MYC regulates Lin28b, which is a key negative regulator of the let-7 family of tumor suppressive microRNAs.