| First Author | Shui B | Year | 2023 |
| Journal | Mol Cell | Volume | 83 |
| Issue | 14 | Pages | 2509-2523.e13 |
| PubMed ID | 37402366 | Mgi Jnum | J:338538 |
| Mgi Id | MGI:7513773 | Doi | 10.1016/j.molcel.2023.06.008 |
| Citation | Shui B, et al. (2023) Oncogenic K-Ras suppresses global miRNA function. Mol Cell 83(14):2509-2523.e13 |
| abstractText | K-Ras frequently acquires gain-of-function mutations (K-Ras(G12D) being the most common) that trigger significant transcriptomic and proteomic changes to drive tumorigenesis. Nevertheless, oncogenic K-Ras-induced dysregulation of post-transcriptional regulators such as microRNAs (miRNAs) during oncogenesis is poorly understood. Here, we report that K-Ras(G12D) promotes global suppression of miRNA activity, resulting in the upregulation of hundreds of targets. We constructed a comprehensive profile of physiological miRNA targets in mouse colonic epithelium and tumors expressing K-Ras(G12D) using Halo-enhanced Argonaute pull-down. Combining this with parallel datasets of chromatin accessibility, transcriptome, and proteome, we uncovered that K-Ras(G12D) suppressed the expression of Csnk1a1 and Csnk2a1, subsequently decreasing Ago2 phosphorylation at Ser825/829/832/835. Hypo-phosphorylated Ago2 increased binding to mRNAs while reducing its activity to repress miRNA targets. Our findings connect a potent regulatory mechanism of global miRNA activity to K-Ras in a pathophysiological context and provide a mechanistic link between oncogenic K-Ras and the post-transcriptional upregulation of miRNA targets. |
