title: miR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops.
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.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China.
authors.forename: Libing
authors.initials: L
authors.lastname: Song
authors.forename: Chuyong
authors.initials: C
authors.lastname: Lin
authors.forename: Hui
authors.initials: H
authors.lastname: Gong
authors.forename: Chanjuan
authors.initials: C
authors.lastname: Wang
authors.forename: Liping
authors.initials: L
authors.lastname: Liu
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Sha
authors.initials: S
authors.lastname: Tao
authors.forename: Bo
authors.initials: B
authors.lastname: Hu
authors.forename: Shi-Yuan
authors.initials: SY
authors.lastname: Cheng
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.forename: Jun
authors.initials: J
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions; D001483:Base Sequence; D045744:Cell Line, Tumor; D010450:Endopeptidases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D005910:Glioma / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000378:metabolism*; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D015398:Signal Transduction; D025801:Ubiquitin / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C560945:MIRN486 microRNA, human; D035683:MicroRNAs; D016328:NF-kappa B; D034741:RNA, Small Interfering; D025801:Ubiquitin; D010450:Endopeptidases; C476458:OTUD7B protein, human