期刊
SCIENCE
卷 361, 期 6399, 页码 290-295出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/science.aap8411
关键词
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资金
- Department of Defense (DOD) Career Development Award [W81XWH-15-1-0599]
- University Cancer Research Fund innovator award [NINDS-P30NS045892]
- National Cancer Institute [R01CA211732, R21CA223675, R35CA197684]
- DOD Fellowship Award [W81XWH-17-1-0016]
- NCI [R35 CA210068]
- National Medical Research Council [OFYIRG17May057]
- Biomedical Research Council (BRMC YIG grant) from Singapore [1510851024]
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 kappa B activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
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