VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma.
Jing ZhangTao WuJeremy M SimonMamoru TakadaRyoichi SaitoCheng FanXian-De LiuEric JonaschLing XieXian ChenXiaosai YaoBin Tean TehPatrick TanXingnan ZhengMingjie LiCortney LawrenceJie FanGeng-Xi JiangXijuan LiuLianxin HuJun WangChengheng LiaoKai HongGiada ZurloJoel S ParkerJames T AumanCharles M PerouW Kimryn RathmellWilliam Y KimMarc W KirschnerWilliam G KaelinAlbert S BaldwinYang ZhangPublished in: Science (New York, N.Y.) (2018)
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.