Regulation of miR-34b/c-targeted gene expression program by SUMOylation

: The miR-34 family of microRNAs suppresses the expression of proteins involved in pluripotency and oncogenesis. miR-34 expression is frequently reduced in cancers; however, the regulation of their expression is not well understood. We used genome-wide miRNA profiling and mechanistic analysis to show that SUMOylation regulates miR-34b/c expression, which impacts the expression of c-Myc and other tested miR-34 targets. We used site-directed mutagenesis and other methods to show that protein kinase B (also known as Akt) phosphorylation of FOXO3a plays an important role in SUMOylation-dependent expression of miR-34b/c. This study reveals how the miR-34-targeted gene expression program is regulated by SUMOylation and shows that SUMOylation need not regulate target proteins through direct modification, but instead can act through the expression of their targeting miRNAs.