MiR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops

Libing Song, Chuyong Lin, Hui Gong, Chanjuan Wang, Liping Liu, Jueheng Wu, Sha Tao, Bo Hu, Shi Yuan Cheng, Mengfeng Li, Jun Li*

*Corresponding author for this work

Research output: Contribution to journalArticle

63 Scopus citations

Abstract

Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as important negative regulators that balance the strength and the duration of NF-κB signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancers, which commonly exhibit constitutively activated NF-κB, remains puzzling. Herein, we report that miR-486 directly suppresses NF-κB-negative regulators, CYLD and Cezanne, as well as multiple A20 activity regulators, including ITCH, TNIP-1, TNIP-2 and TNIP-3, resulting in promotion of ubiquitin conjugations in NF-κB signaling and sustained NF-κB activity. Furthermore, we demonstrate that upregulation of miR-486 promotes glioma aggressiveness both in vitro and in vivo through activation of NF-κB signaling pathway. Importantly, miR-486 levels in primary gliomas significantly correlate with NF-κB activation status. These findings uncover a novel mechanism for constitutive NF-κB activation in gliomas and support a functionally and clinically relevant epigenetic mechanism in cancer progression.

Original languageEnglish (US)
Pages (from-to)274-289
Number of pages16
JournalCell Research
Volume23
Issue number2
DOIs
StatePublished - Feb 1 2013

    Fingerprint

Keywords

  • NF-κB
  • aggressiveness
  • gliomas
  • miR-486
  • ubiquitin

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Song, L., Lin, C., Gong, H., Wang, C., Liu, L., Wu, J., Tao, S., Hu, B., Cheng, S. Y., Li, M., & Li, J. (2013). MiR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops. Cell Research, 23(2), 274-289. https://doi.org/10.1038/cr.2012.174