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- Title
miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops.
- Authors
Song, Libing; Lin, Chuyong; Gong, Hui; Wang, Chanjuan; Liu, Liping; Wu, Jueheng; Tao, Sha; Hu, Bo; Cheng, Shi-Yuan; Li, Mengfeng; Li, Jun
- 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.
- Subjects
NF-kappa B; ENZYME activation; CELLULAR signal transduction; GLIOMAS; CANCER invasiveness; PROMOTERS (Genetics)
- Publication
Cell Research, 2013, Vol 23, Issue 2, p274
- ISSN
1001-0602
- Publication type
Article
- DOI
10.1038/cr.2012.174