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 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 B activation. These studies reveal ZHX2 as a potential therapeutic target for ccRCC.
Source: ScienceNOW - Category: Science Authors: Zhang, J., Wu, T., Simon, J., Takada, M., Saito, R., Fan, C., Liu, X.-D., Jonasch, E., Xie, L., Chen, X., Yao, X., Teh, B. T., Tan, P., Zheng, X., Li, M., Lawrence, C., Fan, J., Geng, J., Liu, X., Hu, L., Wang, J., Liao, C., Hong, K., Zurlo, G., Parker, J Tags: Cell Biology, Medicine, Diseases reports Source Type: news
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