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 Hu; Jun 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

doi:10.1126/science.aap8411

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

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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 language	English (US)
Pages (from-to)	290-295
Number of pages	6
Journal	Science
Volume	361
Issue number	6399
DOIs	https://doi.org/10.1126/science.aap8411
State	Published - Jul 20 2018
Externally published	Yes

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Zhang, J., Wu, T., Simon, J., Takada, M., Saito, R., Fan, C., Liu, X. D., Jonasch, E., Xie, L., Chen, X., Yao, X., Teh, B. T., Tan, P., Zheng, X., Li, M., Lawrence, C., Fan, J., Geng, J., Liu, X., ... Zhang, Q. (2018). VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science, 361(6399), 290-295. https://doi.org/10.1126/science.aap8411

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

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title = "VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma",

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.",

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

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year = "2018",

month = jul,

day = "20",

doi = "10.1126/science.aap8411",

language = "English (US)",

volume = "361",

pages = "290--295",

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T1 - VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma

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

PY - 2018/7/20

Y1 - 2018/7/20

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.

AB - 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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ER -

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

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