MIR-491: CDKN2A tumor suppressor co-pilot.

Genomic instability frequently results in changes in gene expression or altered regulation of oncogenes and tumor suppressor genes. Research into the tumorigenic impact of these genes has led to the current acceptance of many of these genes as drivers of tumorigenesis. In the past decade, studies of small, non-coding RNAs, such as microRNAs (miRNAs), have gained notice in the cancer research field. As miRNAs are often found in intragenic locations, it is likely that gene amplification and loss events such as those which disrupt known oncogenes and tumor suppressor genes, may also affect miRNAs. We recently reported that MIR-491, located just distal to the CDKN2A locus, is frequently co-deleted with CDKN2A [1]. As the CDKN2A locus encodes two well-studied and commonly altered tumor suppressors (p16INK4A and p14ARF), we sought to determine whether loss of MIR-491 plays a functional role in tumorigenesis or is a passenger event. MIR-491 encodes two mature miRNA; miR-491-3p and miR-491-5p, for which previous studies and in silico prediction tools identify several well-known oncogenes as targets. Our study aimed to determine whether MIR491 functions as a tumor suppressor gene in glioblastoma (GBM), by suppressing key cancer hallmarks through coordinate regulation of the predicted targets. We demonstrated that miR-491-5p directly targets EGFR, CDK6, and Bcl-xL; and that miR-491-3p directly targets IGFBP2 and CDK6. Importantly, these predicted, and now confirmed targets of miR-491 each are major oncogenes in GBM. Re-expression of miR-491 impaired glioma cell proliferation and invasive capacity and impaired growth and self-renewal of glioma stem cells (GSCs). Ultimately, forced expression of miR-491-3p and -5p mimics in a murine GBM xenograft model resulted in prolonged survival. By targeting key oncogenes, the mature products of MIR-491 coordinate effects on multiple hallmarks of cancer. Co-deletion of MIR-491 with CDKN2A also gives additional insight into observations surrounding major oncogenic contributors to GBM. Molecular alterations in EGFR have the potential to serve as therapeutic targets in GBM [2]. EGFR amplification occurs in 40-70% of primary GBM, yet some GBM tumors exhibit increased EGFR protein in the absence of gene amplification [3]. Deregulated miRNA, including miR-491, may impact EGFR overexpression. Another miR-491 target, IGFBP2, is one of the most consistently overexpressed factors in GBM, and is a demonstrated driver for tumorigenesis [4]. We previously identified an inverse relationship between IGFBP2 and p16INK4A and p14ARF in multiple cancer types Editorial