Abstract
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.
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.
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