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Mechanobiology

Oncogenic K-Ras suppresses global miRNA function

AUTHORS

Shui BBing , Beyett TSTyler S , Chen ZZhengyi , Li XXiaoyi , La Rocca GGaspare , Gazlay WMWilliam M , Eck MJMichael J , Lau KSKen S , Ventura AAndrea , Haigis KMKevin M . Molecular cell. 2023 06 26; ().

ABSTRACT

K-Ras frequently acquires gain-of-function mutations (K-Ras 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 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 using Halo-enhanced Argonaute pull-down. Combining this with parallel datasets of chromatin accessibility, transcriptome, and proteome, we uncovered that K-Ras 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.