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 Smith, Gianpiero Di Leva, Francesca Galuppini, Athanasios R. Paliouras, Kang Zeng, Raymond T. O’Keefe, Michela Garofalo
Abstract
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.