期刊
CELL RESEARCH
卷 23, 期 2, 页码 274-289出版社
INST BIOCHEMISTRY & CELL BIOLOGY
DOI: 10.1038/cr.2012.174
关键词
miR-486; NF-kappa B; ubiquitin; aggressiveness; gliomas
类别
资金
- Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (GDUPS)
- Natural Science Foundation of China [81071780, 81030048, 91229101, U1201121, 81272196, 81272198]
- Science and Technology Department of Guangdong Province [S2011020002757, S2012020010946]
- National Science and Technique Major Project [201005022-2]
Deubiquitinases, such as CYLD, A20 and Cezanne, have emerged as important negative regulators that balance the strength and the duration of NF-kappa B signaling through feedback mechanisms. However, how these serial feedback loops are simultaneously disrupted in cancers, which commonly exhibit constitutively activated NF-kappa B, remains puzzling. Herein, we report that miR-486 directly suppresses NF-kappa B-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-kappa B signaling and sustained NF-kappa B activity. Furthermore, we demonstrate that upregulation of miR-486 promotes glioma aggressiveness both in vitro and in vivo through activation of NF-kappa B signaling pathway. Importantly, miR-486 levels in primary gliomas significantly correlate with NF-kappa B activation status. These findings uncover a novel mechanism for constitutive NF-kappa B activation in gliomas and support a functionally and clinically relevant epigenetic mechanism in cancer progression.
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