VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma

Jing Zhang, Tao Wu, Jeremy Simon, Mamoru Takada, Ryoichi Saito, Cheng Fan, Xian De Liu, Eric Jonasch, Ling Xie, Xian Chen, Xiaosai Yao, Bin Tean Teh, Patrick Tan, Xingnan Zheng, Mingjie Li, Cortney Lawrence, Jie Fan, Jiang Geng, Xijuan Liu, Lianxin HuJun Wang, Chengheng Liao, Kai Hong, Giada Zurlo, Joel S. Parker, J. Todd Auman, Charles M. Perou, W. Kimryn Rathmell, William Y. Kim, Marc W. Kirschner, William G. Kaelin, Albert S. Baldwin, Qing Zhang

Research output: Contribution to journalArticle

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Abstract

Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.

Original languageEnglish (US)
Pages (from-to)290-295
Number of pages6
JournalScience
Volume361
Issue number6399
DOIs
StatePublished - Jul 20 2018
Externally publishedYes

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Homeobox Genes
Zinc Fingers
Renal Cell Carcinoma
Transcription Factors
Ubiquitin-Protein Ligases
Protein Stability
Chromatin Immunoprecipitation
Hydroxylation
Microarray Analysis
Genome
Mutation
Growth
Neoplasms
Proteins
In Vitro Techniques

ASJC Scopus subject areas

  • General

Cite this

VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. / Zhang, Jing; Wu, Tao; Simon, Jeremy; Takada, Mamoru; Saito, Ryoichi; Fan, Cheng; Liu, Xian De; Jonasch, Eric; Xie, Ling; Chen, Xian; Yao, Xiaosai; Teh, Bin Tean; Tan, Patrick; Zheng, Xingnan; Li, Mingjie; Lawrence, Cortney; Fan, Jie; Geng, Jiang; Liu, Xijuan; Hu, Lianxin; Wang, Jun; Liao, Chengheng; Hong, Kai; Zurlo, Giada; Parker, Joel S.; Todd Auman, J.; Perou, Charles M.; Kimryn Rathmell, W.; Kim, William Y.; Kirschner, Marc W.; Kaelin, William G.; Baldwin, Albert S.; Zhang, Qing.

In: Science, Vol. 361, No. 6399, 20.07.2018, p. 290-295.

Research output: Contribution to journalArticle

Zhang, J, Wu, T, Simon, J, Takada, M, Saito, R, Fan, C, Liu, XD, Jonasch, E, Xie, L, Chen, X, Yao, X, Teh, BT, Tan, P, Zheng, X, Li, M, Lawrence, C, Fan, J, Geng, J, Liu, X, Hu, L, Wang, J, Liao, C, Hong, K, Zurlo, G, Parker, JS, Todd Auman, J, Perou, CM, Kimryn Rathmell, W, Kim, WY, Kirschner, MW, Kaelin, WG, Baldwin, AS & Zhang, Q 2018, 'VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma', Science, vol. 361, no. 6399, pp. 290-295. https://doi.org/10.1126/science.aap8411
Zhang, Jing ; Wu, Tao ; Simon, Jeremy ; Takada, Mamoru ; Saito, Ryoichi ; Fan, Cheng ; Liu, Xian De ; Jonasch, Eric ; Xie, Ling ; Chen, Xian ; Yao, Xiaosai ; Teh, Bin Tean ; Tan, Patrick ; Zheng, Xingnan ; Li, Mingjie ; Lawrence, Cortney ; Fan, Jie ; Geng, Jiang ; Liu, Xijuan ; Hu, Lianxin ; Wang, Jun ; Liao, Chengheng ; Hong, Kai ; Zurlo, Giada ; Parker, Joel S. ; Todd Auman, J. ; Perou, Charles M. ; Kimryn Rathmell, W. ; Kim, William Y. ; Kirschner, Marc W. ; Kaelin, William G. ; Baldwin, Albert S. ; Zhang, Qing. / VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. In: Science. 2018 ; Vol. 361, No. 6399. pp. 290-295.
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abstract = "Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.",
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AU - Zhang, Jing

AU - Wu, Tao

AU - Simon, Jeremy

AU - Takada, Mamoru

AU - Saito, Ryoichi

AU - Fan, Cheng

AU - Liu, Xian De

AU - Jonasch, Eric

AU - Xie, Ling

AU - Chen, Xian

AU - Yao, Xiaosai

AU - Teh, Bin Tean

AU - Tan, Patrick

AU - Zheng, Xingnan

AU - Li, Mingjie

AU - Lawrence, Cortney

AU - Fan, Jie

AU - Geng, Jiang

AU - Liu, Xijuan

AU - Hu, Lianxin

AU - Wang, Jun

AU - Liao, Chengheng

AU - Hong, Kai

AU - Zurlo, Giada

AU - Parker, Joel S.

AU - Todd Auman, J.

AU - Perou, Charles M.

AU - Kimryn Rathmell, W.

AU - Kim, William Y.

AU - Kirschner, Marc W.

AU - Kaelin, William G.

AU - Baldwin, Albert S.

AU - Zhang, Qing

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N2 - Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase protein is a hallmark of clear cell renal cell carcinoma (ccRCC). Identifying how pathways affected by VHL loss contribute to ccRCC remains challenging. We used a genome-wide in vitro expression strategy to identify proteins that bind VHL when hydroxylated. Zinc fingers and homeoboxes 2 (ZHX2) was found as a VHL target, and its hydroxylation allowed VHL to regulate its protein stability. Tumor cells from ccRCC patients with VHL loss-of-function mutations usually had increased abundance and nuclear localization of ZHX2. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated chromatin immunoprecipitation sequencing and microarray analysis showed that ZHX2 promoted nuclear factor κB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.

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