A KRAS-responsive long non-coding RNA controls microRNA processing

Lei Shi, Peter Magee, Matteo Fassan, Sudhakar Sahoo, Hui Sun Leong, Dave Lee, Robert Sellers, Laura Brullé-Soumaré, Stefano Cairo, Tiziana Monteverde, Stefano Volinia, Duncan D. Smith, Gianpiero Leva, Francesca Galuppini, Athanasios R. Paliouras, Kang Zeng, Raymond O’Keefe and Michela Garofalo ()
Additional contact information
Lei Shi: University of Manchester
Peter Magee: University of Manchester
Matteo Fassan: University of Padua
Sudhakar Sahoo: University of Manchester
Hui Sun Leong: University of Manchester
Dave Lee: University of Manchester
Robert Sellers: University of Manchester
Laura Brullé-Soumaré: Xentech, 4 rue Pierre Fontaine
Stefano Cairo: Xentech, 4 rue Pierre Fontaine
Tiziana Monteverde: University of Manchester
Stefano Volinia: University of Ferrara
Duncan D. Smith: University of Manchester
Gianpiero Leva: Keele University
Francesca Galuppini: University of Padua
Athanasios R. Paliouras: University of Manchester
Kang Zeng: University of Manchester
Raymond O’Keefe: University of Manchester
Michela Garofalo: University of Manchester

Nature Communications, 2021, vol. 12, issue 1, 1-19

Abstract: Abstract Wild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRASWT overexpression in lung cancer progression is largely unexplored. Here, we identify and characterize a KRAS-responsive lncRNA, KIMAT1 (ENSG00000228709) and show that it correlates with KRAS levels both in cell lines and in lung cancer specimens. Mechanistically, KIMAT1 is a MYC target and drives lung tumorigenesis by promoting the processing of oncogenic microRNAs (miRNAs) through DHX9 and NPM1 stabilization while halting the biogenesis of miRNAs with tumor suppressor function via MYC-dependent silencing of p21, a component of the Microprocessor Complex. KIMAT1 knockdown suppresses not only KRAS expression but also KRAS downstream signaling, thereby arresting lung cancer growth in vitro and in vivo. Taken together, this study uncovers a role for KIMAT1 in maintaining a positive feedback loop that sustains KRAS signaling during lung cancer progression and provides a proof of principle that interfering with KIMAT1 could be a strategy to hamper KRAS-induced tumorigenesis.

Date: 2021
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22337-3

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DOI: 10.1038/s41467-021-22337-3

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