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