Oncogenic KRAS Rewires mRNA Stability and Translation through AGO2-Mediated Disruption of the miRNA pathway.

Authors

Ziyue Z Yang, Angelina S Bortoletto, Mara G Cardenas, Mason D Bartels, Savannah Mwesigwa, Charlotte A Le Roux, Caroline G Snider, Man-Tzu Wang, Huihui Fan, Eric L Van Nostrand, Frank McCormick, Ronald J Parchem

Published in

Cancer research. Aug 24, 2026. Epub Aug 24, 2026.

Abstract

KRAS mutations occur in over 90% of pancreatic ductal adenocarcinomas (PDACs). Despite recent advances in targeting oncogenic KRAS, tumors eventually acquire resistance. A more comprehensive understanding of the mechanisms connecting KRAS signaling to tumor progression could facilitate the development of effective therapies to improve the treatment of KRAS-driven malignancies. Here, we dissected how oncogenic KRAS reprograms post-transcriptional regulation in PDAC. Oncogenic KRAS altered AGO2 phosphorylation at tyrosine 393, expanded the miRNA-mRNA interaction network, and impaired both mRNA destabilization and translational repression. Mapping endogenous miRNA-mRNA interactions using AGO2 chimeric eCLIP combined with genome-wide measurements of mRNA stability and translational efficiency using SLAM-seq and Ribo-eCLIP revealed that miRNA targets in KRAS-mutant cells exhibited increased stability and translational efficiency, even when cognate miRNA levels were unchanged. The rewiring enriched pro-tumorigenic transcripts involved in GTPase signaling, autophagy, and metabolism, and it was accompanied by the assembly of enlarged, static processing bodies (P-bodies) in cell lines, mouse models, and patient tumors, an effect that could be reversed by inhibiting oncogenic KRAS. Expression of a phospho-mimetic AGO2 Y393E reproduced the effects of oncogenic KRAS, while a phospho-deficient AGO2 Y393A blocked them. These findings identify a mechanistically distinct post-transcriptional effector arm of KRAS signaling, link AGO2 Y393 phosphorylation to both silencing dysfunction and condensate remodeling, and reveal opportunities to target RNA regulation in PDAC.

PMID:
42635442
Bibliographic data and abstract were imported from PubMed on 24 Aug 2026.

Read full publication at:
Please sign in to see all details.

Stats

1-terrible, 9-excellent. How would you rate this publication? Sign in in to submit your rating.

Post a comment

You need to be signed in to post comments. You can sign in here.

Comments

There are no comments yet.