Abstract
Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.
| Original language | English (US) |
|---|---|
| Article number | 4013 |
| Journal | Nature communications |
| Volume | 10 |
| Issue number | 1 |
| DOIs | |
| State | Published - Dec 1 2019 |
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ASJC Scopus subject areas
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)
- Physics and Astronomy(all)
Cite this
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CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity. / Sang, Youzhou; Li, Yanxin; Zhang, Yingwen; Alvarez, Angel A; Yu, Bo; Zhang, Weiwei; Hu, Bo; Cheng, Shi-Yuan; Feng, Haizhong.
In: Nature communications, Vol. 10, No. 1, 4013, 01.12.2019.Research output: Contribution to journal › Article
TY - JOUR
T1 - CDK5-dependent phosphorylation and nuclear translocation of TRIM59 promotes macroH2A1 ubiquitination and tumorigenicity
AU - Sang, Youzhou
AU - Li, Yanxin
AU - Zhang, Yingwen
AU - Alvarez, Angel A
AU - Yu, Bo
AU - Zhang, Weiwei
AU - Hu, Bo
AU - Cheng, Shi-Yuan
AU - Feng, Haizhong
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.
AB - Despite the development of adjuvant therapies, glioblastoma (GBM) patients remain incurable, thus justifying the urgent need of new therapies. CDK5 plays a critical role in GBM and is a potential target for GBM. However, the mechanism by which CDK5 promotes GBM tumorigenicity remains largely unknown. Here, we identify TRIM59 as a substrate of CDK5. EGFR-activated CDK5 directly binds to and phosphorylates TRIM59, a ubiquitin ligase at serine 308, which recruits PIN1 for cis–trans isomerization of TRIM59, leading to TRIM59 binding to importin α5 and nuclear translocation. Nuclear TRIM59 induces ubiquitination and degradation of the tumor suppressive histone variant macroH2A1, leading to enhanced STAT3 signaling activation and tumorigenicity. These findings are confirmed by inhibition of CDK5-activated TRIM59 activity that results in suppression of intracranial tumor growth. Correlative expressions of the components of this pathway are clinically prognostic. Our findings suggest targeting CDK5/TRIM59 signaling axis as a putative strategy for treating GBM.
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UR - http://www.scopus.com/inward/citedby.url?scp=85071766264&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12001-2
DO - 10.1038/s41467-019-12001-2
M3 - Article
C2 - 31488827
AN - SCOPUS:85071766264
VL - 10
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 4013
ER -