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

Author

Listed:
  • Lei Shi

    (University of Manchester
    at Manchester and University College London)

  • Peter Magee

    (University of Manchester
    at Manchester and University College London)

  • 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
    at Manchester and University College London)

  • 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
    at Manchester and University College London)

  • Kang Zeng

    (University of Manchester)

  • Raymond O’Keefe

    (University of Manchester)

  • Michela Garofalo

    (University of Manchester
    at Manchester and University College London)

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.

Suggested Citation

  • 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 & Gia, 2021. "A KRAS-responsive long non-coding RNA controls microRNA processing," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-22337-3
    DOI: 10.1038/s41467-021-22337-3
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