ZBRK1, a novel tumor suppressor, activates VHL gene transcription through formation of a complex with VHL and p300 in renal cancer

// Ke Chen 1, 2, * , Gan Yu 1, 2, * , Kiranmai Gumireddy 3 , Anping Li 3 , Weimin Yao 1, 2 , Lu Gao 4 , Shuliang Chen 5 , Jun Hao 6 , Ji Wang 7 , Qihong Huang 3 , Hua Xu 1, 2 , Zhangqun Ye 1, 2 1 Department of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 2 Institute of Urology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 3 The Wistar Institute, Philadelphia, PA, USA 4 Department of Cardiology, Institute of Cardiovascular Disease, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 5 School of Basic Medical Sciences, Wuhan University, Wuhan, China 6 Cardiovascular Research Institute of Wuhan University, Wuhan, China 7 Department of Cell Death and Cancer Genetics, The Hormel Institute, University of Minnesota, Austin, MN, USA * These authors have contributed equally to this work Correspondence to: Hua Xu, e-mail: xuhuawhu@163.com Keywords: ZBRK1, VHL, p300, renal cancer, tumor suppressor Received: September 12, 2014      Accepted: January 10, 2015      Published: February 10, 2015 ABSTRACT 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.