Characterization of Dual PTEN and p53-Targeting MicroRNAs Identifies MicroRNA-638/Dnm2 as a Two-Hit Oncogenic Locus

Abstract

Tumor suppressor genes (TSGs) are often concomitantly lost or mutated in human cancers and have been shown to act synergistically to promote tumorigenesis. In addition to genomic alterations, posttranscriptional regulation by microRNAs (miRNAs) represents another mechanism by which TSG expression is dysregulated in cancers. Although miRNAs that target critical TSGs such as PTEN or p53 have been identified, little is known about miRNAs that concomitantly regulate both these key TSGs. In this study, we characterize microRNA 518c∗ (miR-518c∗) and miR-638 as dual PTEN- and p53-targeting miRNAs that are upregulated in multiple human cancers. We focus on miR-638 and show that it associates independently with these two tumor suppressor transcripts as well as BRCA1, a known miR-638 target. We find that miR-638 overexpression promotes tumorigenesis and demonstrate cooperativity between miR-638 and its host gene Dnm2, suggesting that the Dnm2 locus encodes two distinct oncogenic components that play important roles in tumorigenesis.