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

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

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.

Citation

Shi, L., Magee, P., Fassan, M., Sahoo, S., Leong, H. S., Lee, D., …Garofalo, M. (2021). A KRAS-responsive long non-coding RNA controls microRNA processing. Nature communications, 12, Article 2038. https://doi.org/10.1038/s41467-021-22337-3

• Journal Article Type: Article
• Acceptance Date: Mar 2, 2021
• Publication Date: Apr 1, 2021
• Journal: Nature Communications
• Print ISSN: 2041-1723
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Article Number: 2038
• DOI: https://doi.org/10.1038/s41467-021-22337-3
• Keywords: Long non-coding RNAs; Non-small-cell lung cancer
• Publisher URL: https://www.nature.com/articles/s41467-021-22337-3