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

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