Oncogenic K-Ras suppresses global miRNA function Journal Article

   


Authors: Shui, B.; Beyett, T. S.; Chen, Z.; Li, X.; La Rocca, G.; Gazlay, W. M.; Eck, M. J.; Lau, K. S.; Ventura, A.; Haigis, K. M.
Article Title: Oncogenic K-Ras suppresses global miRNA function
Abstract: K-Ras frequently acquires gain-of-function mutations (K-RasG12D 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-RasG12D 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-RasG12D using Halo-enhanced Argonaute pull-down. Combining this with parallel datasets of chromatin accessibility, transcriptome, and proteome, we uncovered that K-RasG12D 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. © 2023 Elsevier Inc.
Keywords: colorectal cancer; colon; k-ras; mirna; ago2; casein kinase; clip-seq
Journal Title: Molecular Cell
Volume: 83
Issue: 14
ISSN: 1097-2765
Publisher: Cell Press  
Date Published: 2023-07-20
Start Page: 2509
End Page: 2523.e13
Language: English
DOI: 10.1016/j.molcel.2023.06.008
PUBMED: 37402366
PROVIDER: scopus
PMCID: PMC10527862
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85165063986&doi=10.1016%2fj.molcel.2023.06.008&partnerID=40&md5=6d694f734fe40eb7384d2d58c5203c75
Notes: Article -- Source: Scopus
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MSK Authors
  1. Andrea Ventura
    56 Ventura
  2. Gaspare La Rocca
    22 La Rocca
  3. Xiaoyi Li
    5 Li
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