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

Oncotarget
Ke ChenZhangqun Ye

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.

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Citations

Jun 22, 2016·Oncotarget·Huili LiJiliang Wang
Aug 23, 2017·Molecular and Cellular Biology·Jae Ho LeeJae Bum Kim
Jan 9, 2016·Journal of Cell Science·Ke ChenZhangqun Ye
Nov 7, 2018·Scientific Reports·Federico InnocentiKouros Owzar
Nov 24, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Ke ChenZhangqun Ye
Mar 7, 2021·International Journal of Molecular Sciences·Joanna SobocińskaUrszula Oleksiewicz

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Methods Mentioned

BETA
Y2H
co-immunoprecipitation
two-hybrid
Co-IP
confocal microscopy
PCR
xenograft
transfection
immunoprecipitation assay
immunoprecipitation

Software Mentioned

SPSS
Living Image

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