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Science. 2018 Jul 20;361(6399):290-295. doi: 10.1126/science.aap8411.

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

Author information

1
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
2
Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC 27599, USA.
3
Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Genetics, Neuroscience Center, University of North Carolina, Chapel Hill, NC 27599, USA.
5
Departments of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
6
Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, NC 27599, USA.
7
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore 138672, Singapore.
8
Institute of Molecular and Cell Biology, Singapore 138673, Singapore.
9
Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore 169610, Singapore.
10
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore 169857, Singapore.
11
Department of Pathology, Huashan Hospital, Fudan University, Shanghai, China.
12
Department of Urology, Shanghai Tenth People's Hospital, Tongji University, Shanghai, China.
13
Division of Hematology and Oncology, Department of Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
14
Howard Hughes Medical Institute, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
15
Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA. qing_zhang@med.unc.edu.
16
Department of Pharmacology, University of North Carolina, Chapel Hill, NC 27599, USA.

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.

PMID:
30026228
PMCID:
PMC6154478
DOI:
10.1126/science.aap8411
[Indexed for MEDLINE]
Free PMC Article

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