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

Lei Shi,Gianpiero Di Leva,Duncan D Smith,Sudhakar Sahoo,Kang Zeng,Dave Lee,Peter Magee,Laura Brullé-Soumaré,Athanasios R Paliouras,Robert Sellers,Stefano Cairo,Francesca Galuppini,Raymond O’Keefe,Tiziana Monteverde,Matteo Fassan,Michela Garofalo,Hui Sun Leong,Stefano Volinia

doi:10.1038/s41467-021-22337-3

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.

Highlights

Wild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival
To verify whether KIMAT1 could be clinically relevant, we identified genes that were both upregulated upon KRAS OE in H1299 cells and in the lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC) datasets from the the Cancer Genome Atlas (TCGA) compared to normal lung tissues
We leveraged the pleiotropic functions of long non-coding RNAs (lncRNAs) to identify KRAS-regulated pathways that could be exploited for therapeutic purpose

Summary

Introduction

Wild-type KRAS (KRASWT) amplification has been shown to be a secondary means of KRAS activation in cancer and associated with poor survival. 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. LncRNAs are clearly a crucial layer of biological regulation, only a few have been functionally characterized and the molecular mechanism(s) behind their biology remains largely unknown. Another class of regulatory non-coding RNAs, miRNAs, have gained significant importance in the past decades as master regulators of gene expression[7]. We characterize a human KRAS-responsive lncRNA, KIMAT1, which sustains essential oncogenic signaling by modulating components of the MC and miRNA biogenesis, thereby promoting lung cancer progression. We have uncovered a function for a lncRNA in miRNA processing, which may shed light on key aspects of cancer biology

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