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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 274-289 |
| Number of pages | 16 |
| Journal | Cell Research |
| Volume | 23 |
| Issue number | 2 |
| DOIs | |
| State | Published - Feb 1 2013 |
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Keywords
- NF-κB
- aggressiveness
- gliomas
- miR-486
- ubiquitin
ASJC Scopus subject areas
- Molecular Biology
- Cell Biology
Cite this
}
MiR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops. / Song, Libing; Lin, Chuyong; Gong, Hui; Wang, Chanjuan; Liu, Liping; Wu, Jueheng; Tao, Sha; Hu, Bo; Cheng, Shi-Yuan; Li, Mengfeng; Li, Jun.
In: Cell Research, Vol. 23, No. 2, 01.02.2013, p. 274-289.Research output: Contribution to journal › Article
TY - JOUR
T1 - MiR-486 sustains NF-κB activity by disrupting multiple NF-κB-negative feedback loops
AU - Song, Libing
AU - Lin, Chuyong
AU - Gong, Hui
AU - Wang, Chanjuan
AU - Liu, Liping
AU - Wu, Jueheng
AU - Tao, Sha
AU - Hu, Bo
AU - Cheng, Shi-Yuan
AU - Li, Mengfeng
AU - Li, Jun
PY - 2013/2/1
Y1 - 2013/2/1
N2 - 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.
AB - 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.
KW - NF-κB
KW - aggressiveness
KW - gliomas
KW - miR-486
KW - ubiquitin
UR - http://www.scopus.com/inward/record.url?scp=84873729426&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84873729426&partnerID=8YFLogxK
U2 - 10.1038/cr.2012.174
DO - 10.1038/cr.2012.174
M3 - Article
C2 - 23247627
AN - SCOPUS:84873729426
VL - 23
SP - 274
EP - 289
JO - Cell Research
JF - Cell Research
SN - 1001-0602
IS - 2
ER -