Loss of VHL-mediated degradation of ZHX2 promotes clear cell renal cell carcinoma growth.

  • Major finding: Loss of VHL-mediated degradation of ZHX2 promotes clear cell renal cell carcinoma growth.

  • Mechanism: Accumulated nuclear ZHX2 interacts with RELA/p65 to drive expression of NF-κB target genes.

  • Impact: ZHX2 is a potential therapeutic target for patients with clear cell renal cell carcinoma.

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Inactivation of the von Hippel Landau (VHL) gene, which encodes a component of the E3 ubiquitin ligase complex that mediates the degradation of prolylhydroxylated proteins, occurs in almost all patients with clear cell renal cell carcinoma (ccRCC). Hypoxia-inducible factors (HIF) are the most commonly therapeutically targeted VHL substrate; however, drug resistance frequently arises in patients treated with VEGF inhibitors, which indirectly target HIFs. To identify additional VHL targets, Zhang, Wu, and colleagues developed an in vitro genome-wide screening strategy to identify proteins binding with VHL complexes that are out-competed by hydroxylated, but not nonhydroxylated, HIF1α peptide. Accordingly, the zinc fingers and homeoboxes 2 (ZHX2) transcription factor was identified as a VHL substrate and shown to bind with VHL and be destabilized by VHL upon prolyl hydroxylation. Evaluation of patient samples revealed the nuclear accumulation of ZHX2 in VHL-deficient ccRCC but not in VHL–wild-type ccRCC or nontumor tissues; further, knockdown of ZHX2 resulted in decreased VHL-deficient ccRCC proliferation and soft-agar growth in vitro and orthotopic ccRCC growth in vivo. Gene expression profiling showed that ZHX2 depletion resulted in decreased activation of the NF-κB signaling pathway, immunoprecipitation (IP) studies showed that ZHX2 interacts with the NF-κB RELA/p65 subunit and ZHX2 also controls RELA/p65 nuclear localization. Moreover, chromatin IP-sequencing studies demonstrated the co-occupancy of ZHX2 and RELA/p65 at sites that were enriched for NF-κB consensus motifs in active promoters of genes associated with worse prognosis for patients with ccRCC. Together, these results identify and characterize ZHX2 as a VHL substrate and a potential driver of ccRCC and suggest potential therapeutic approaches for patients with VHL-deficient ccRCC.

Zhang J, Wu T, Simon J, Takada M, Saito R, Fan C, et al. VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science 2018;361:290–5.

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