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

• Published in: Cell research Vol. 23; no. 2; pp. 274 - 289
• Main Authors: Song, Libing, Lin, Chuyong, Gong, Hui, Wang, Chanjuan, Liu, Liping, Wu, Jueheng, Tao, Sha, Hu, Bo, Cheng, Shi-Yuan, Li, Mengfeng, Li, Jun
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.02.2013; Nature Publishing Group
• Subjects: 3' Untranslated Regions; 631/337/384/331; 631/45/612/645; 631/80/86; 692/699/67/1922; A20 protein; Base Sequence; Biomedical and Life Sciences; Cancer; Cell Biology; Cell Line, Tumor; Endopeptidases - chemistry; Endopeptidases - genetics; Endopeptidases - metabolism; Epigenetics; Feedback; Feedback loops; Gene Expression Profiling; Glioma; Glioma - metabolism; Glioma - mortality; Glioma - pathology; Human Umbilical Vein Endothelial Cells; Humans; Kaplan-Meier Estimate; Life Sciences; MicroRNAs - metabolism; Negative feedback; NF-kappa B - genetics; NF-kappa B - metabolism; NF-κB protein; Original; original-article; RNA Interference; RNA, Small Interfering - metabolism; Signal Transduction; Signaling; Ubiquitin; Ubiquitin - metabolism; NF-κB; gliomas; aggressiveness; ubiquitin; miR-486
• ISSN: 1001-0602; 1748-7838
• DOI: 10.1038/cr.2012.174

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.