Autoregulatory Suppression of c-Myc by miR-185-3p

The expression of the c-myc oncogene at both protein and mRNA levels is transient and begins to be turned off 3-6 h after growth stimulation of cultured cells. The exact mechanism(s) underlying this down-regulation of c-Myc remains incompletely understood. Here we report the identification of miR-185-3p as a novel feedback regulator of c-Myc. This microRNA (miRNA) was initially identified as one of the c-Myc target miRNA transcripts through analysis of RNA samples isolated from cells prior to and after serum stimulation and further verified by real-time PCR, luciferase reporter, and ChIP assays. Interestingly, overexpression of wild type, but not mutant, miR-185-3p decreased the protein, but not mRNA, level of c-Myc in a dose-dependent fashion and also drastically abated the serum induction of c-Myc level in human cancer cells by targeting the coding sequence of c-Myc mRNA, consequently suppressing c-Myc-mediated proliferation. A miR-185-3p inhibitor rescued the inhibition of c-Myc expression by endogenous miR-185-3p. Thus, our results unveil miR-185-3p as the first miRNA that monitors c-Myc levels via an autoregulatory feedback mechanism in response to serum stimulation.