Zhang, J., Wu, T., Simon, J., Takada, M., Saito, R., Fan, C., … Zhang, Q. (2018). VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science, 361(6399), 290–295. doi:10.1126/science.aap8411
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.
This research / project is supported by the National Medical Research Council - Open Fund - Young Individual Research Grant
Grant Reference no. : OFYIRG17May057
This research / project is supported by the Biomedical Research Council - BMRC YIG grant
Grant Reference no. : 1510851024
This is the author’s version of the work. It is posted here by permission of the AAAS for personal use, not for redistribution. The definitive version was published in Science on Vol.361 20 July 2018, http://dx.doi.org/10.1126/science.aap8411