ZBRK1, a novel tumor suppressor, activates VHL gene transcription through formation of a complex with VHL and p300 in renal cancer.
Inactivation or mutation of the VHL gene causes various tumors, including clear cell renal cell carcinoma (ccRCC). In the present study, we identified ZBRK1 as a novel VHL interacting protein by yeast two-hybrid screening, and found a single ZBRK1-binding site located in the VHL promoter region. Ectopic expression of ZBRK1 increases transcriptional activity of the VHL, whereas the depletion of endogenous ZBRK1 by shRNA leads to reduction of VHL expression. We also demonstrate that the inhibition of VEGF transcription by ZBRK1 overexpression is dependent on VHL/HIF pathway. Moreover, VHL is confirmed to serve as a bridge component for the association of ZBRK1 and p300, which leads to an increase in ZBRK1 transcriptional activity in the VHL promoter. We further provide striking evidences that ZBRK1 acts as a tumor suppressor in renal carcinoma by a variety of in vitro and in vivo assays, and ZBRK1 may represent a molecular marker to distinguish patients with ccRCC at high risk from those with a better survival prognosis. Taken together, these findings suggest that ZBRK1 suppresses renal cancer progression perhaps by regulating VHL expression.
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Ke
K
Chen
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Gan
G
Yu
The Wistar Institute, Philadelphia, PA, USA.
Kiranmai
K
Gumireddy
The Wistar Institute, Philadelphia, PA, USA.
Anping
A
Li
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Weimin
W
Yao
Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Lu
L
Gao
School of Basic Medical Sciences, Wuhan University, Wuhan, China.
Shuliang
S
Chen
Cardiovascular Research Institute of Wuhan University, Wuhan, China.
Jun
J
Hao
Department of Cell Death and Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, MN, USA.
Ji
J
Wang
The Wistar Institute, Philadelphia, PA, USA.
Qihong
Q
Huang
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Hua
H
Xu
Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.|Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Zhangqun
Z
Ye
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000378:metabolism*; D002465:Cell Movement; D018450:Disease Progression; D050881:E1A-Associated p300 Protein / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D007680:Kidney Neoplasms / Q000378:metabolism; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism*; D014158:Transcription, Genetic; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism*
D012097:Repressor Proteins; C422407:ZNF350 protein, human; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
VHL; ZBRK1; p300; renal cancer; tumor suppressor