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
N1 - Funding Information:
We thank Ichiro Nakano for providing patient-derived GSCs. This work was supported in part by the National Natural Science Foundation of China (nos. 81372704, 81572467 to H. Feng; nos. 81470315, 81772663 to Y. Li); the Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (no. 2014024), Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support (no. 20161310), New Hundred Talent Program (Outstanding Academic Leader) at Shanghai Municipal Health Bureau (2017BR021), Technology Transfer Project of Science & Technology Dept. at Shanghai Jiao Tong University School of Medicine (ZT201701 to H. Feng); Shanghai Jiao Tong University Medical Engineering Cross Fund (no. YG2017MS32 to Y. Li); US NIH grants (NS093843, NS95634, and CA209345 to S.-Y. Cheng); NIH/NCI training grant T32 CA070085 and NIH LRP award (L32 MD010147 to A.A. Alvarez); JSPS KAKENHI (grant number 24112006, 15H04690 to S. Hatakeyama).
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 -