VHL Substrate Transcription Factor ZHX2 As An Oncogenic Driver In Clear Cell Renal Cell Carcinoma

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 bound VHL only 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 ZHX2 amount and nuclear localization. Functionally, depletion of ZHX2 inhibited VHL-deficient ccRCC cell growth in vitro and in vivo. Mechanistically, integrated ChIP-Seq and microarray analysis showed that ZHX2 promoted NF-kB activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC. Overall design: ZHX2 is identified as a VHL substrate from a genome-wide screen, which promotes NF-kB pathway activation and ccRCC tumorigenesis. We profiled NFkB-p65 and ZHX2 occupancy genome-wide using ChIP-seq in ccRCC 786-0 cells