A KRAS-responsive Long Non-coding RNA Controls MicroRNA Processing

Overview

Journal Nat Commun

Specialty Biology

Date 2021 Apr 2

PMID 33795683

Citations 24

Authors

Lei Shi

Peter Magee

Matteo Fassan

Sudhakar Sahoo

Hui Sun Leong

Dave Lee

Robert Sellers

Laura Brulle-Soumare

Stefano Cairo

Tiziana Monteverde

Stefano Volinia

Duncan D Smith

Gianpiero Di Leva

Francesca Galuppini

Athanasios R Paliouras

Kang Zeng

Raymond OKeefe

Michela Garofalo

Affiliations

Soon will be listed here.

Abstract

Wild-type KRAS (KRAS) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. Nevertheless, the precise role of KRAS 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.

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