Abstract
Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation. Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1792-1804 |
| Number of pages | 13 |
| Journal | Cancer Research |
| Volume | 78 |
| Issue number | 7 |
| DOIs | |
| State | Published - Apr 1 2018 |
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ASJC Scopus subject areas
- Oncology
- Cancer Research
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TRIM59 promotes gliomagenesis by inhibiting tc45 dephosphorylation of STAT3. / Sang, Youzhou; Li, Yanxin; Song, Lina; Alvarez, Angel A; Zhang, Weiwei; Lv, Deguan; Tang, Jianming; Liu, Feng; Chang, Zhijie; Hatakeyama, Shigetsugu; Hu, Bo; Cheng, Shi-Yuan; Feng, Haizhong.
In: Cancer Research, Vol. 78, No. 7, 01.04.2018, p. 1792-1804.Research output: Contribution to journal › Article
TY - JOUR
T1 - TRIM59 promotes gliomagenesis by inhibiting tc45 dephosphorylation of STAT3
AU - Sang, Youzhou
AU - Li, Yanxin
AU - Song, Lina
AU - Alvarez, Angel A
AU - Zhang, Weiwei
AU - Lv, Deguan
AU - Tang, Jianming
AU - Liu, Feng
AU - Chang, Zhijie
AU - Hatakeyama, Shigetsugu
AU - Hu, Bo
AU - Cheng, Shi-Yuan
AU - Feng, Haizhong
PY - 2018/4/1
Y1 - 2018/4/1
N2 - Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation. Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis.
AB - Aberrant EGFR signaling is a common driver of glioblastoma (GBM) pathogenesis; however, the downstream effectors that sustain this oncogenic pathway remain unclarified. Here we demonstrate that tripartite motif-containing protein 59 (TRIM59) acts as a new downstream effector of EGFR signaling by regulating STAT3 activation in GBM. EGFR signaling led to TRIM59 upregulation through SOX9 and enhanced the interaction between TRIM59 and nuclear STAT3, which prevents STAT3 dephosphorylation by the nuclear form of T-cell protein tyrosine phosphatase (TC45), thereby maintaining transcriptional activation and promoting tumorigenesis. Silencing TRIM59 suppresses cell proliferation, migration, and orthotopic xenograft brain tumor formation of GBM cells and glioma stem cells. Evaluation of GBM patient samples revealed an association between EGFR activation, TRIM59 expression, STAT3 phosphorylation, and poor prognoses. Our study identifies TRIM59 as a new regulator of oncogenic EGFR/STAT3 signaling and as a potential therapeutic target for GBM patients with EGFR activation. Significance: These findings identify a novel component of the EGFR/STAT3 signaling axis in the regulation of glioma tumorigenesis.
UR - http://www.scopus.com/inward/record.url?scp=85047857701&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85047857701&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-17-2774
DO - 10.1158/0008-5472.CAN-17-2774
M3 - Article
C2 - 29386185
AN - SCOPUS:85047857701
VL - 78
SP - 1792
EP - 1804
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 7
ER -