ZBRK1, a novel tumor suppressor, activates VHL gene transcription through formation of a complex with VHL and p300 in renal cancer
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Ke Chen1,2,*, Gan Yu1,2,*, Kiranmai Gumireddy3, Anping Li3, Weimin Yao1,2, Lu Gao4, Shuliang Chen5, Jun Hao6, Ji Wang7, Qihong Huang3, Hua Xu1,2, Zhangqun Ye1,2
1Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
2Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
3The Wistar Institute, Philadelphia, PA, USA
4Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
5School of Basic Medical Sciences, Wuhan University, Wuhan, China
6Cardiovascular Research Institute of Wuhan University, Wuhan, China
7Department of Cell Death and Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, MN, USA
*These authors have contributed equally to this work
Hua Xu, e-mail: [email protected]
Keywords: ZBRK1, VHL, p300, renal cancer, tumor suppressor
Received: September 12, 2014 Accepted: January 10, 2015 Published: February 10, 2015
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.
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