VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Inactivation of the von Hippel-Lindau (VHL) E3 ubiquitin ligase is a key event in clear cell renal cell carcinoma (ccRCC) pathogenesis.
• Understanding the downstream pathways affected by VHL loss is crucial for developing effective ccRCC therapies.

Purpose of the Study:

• To identify proteins that interact with VHL upon hydroxylation.
• To investigate the role of identified VHL targets in ccRCC development and progression.
• To explore ZHX2 as a potential therapeutic target for ccRCC.

Main Methods:

• Genome-wide in vitro expression screening to identify VHL-binding proteins.
• Assessment of ZHX2 protein stability regulation by VHL.
• Analysis of ZHX2 abundance and localization in ccRCC patient tumors.
• In vitro and in vivo functional assays involving ZHX2 depletion.
• Integrated chromatin immunoprecipitation sequencing and microarray analysis to elucidate molecular mechanisms.

Main Results:

• Zinc fingers and homeoboxes 2 (ZHX2) was identified as a VHL target, with its hydroxylation enabling VHL-mediated protein stability regulation.
• Increased ZHX2 abundance and nuclear localization were observed in ccRCC tumor cells with VHL mutations.
• Depletion of ZHX2 significantly inhibited the growth of VHL-deficient ccRCC cells both in vitro and in vivo.
• ZHX2 was found to promote nuclear factor κB (NF-κB) activation.

Conclusions:

• ZHX2 is a novel VHL target protein implicated in ccRCC.
• ZHX2 plays a critical role in promoting ccRCC cell growth and NF-κB activation.
• ZHX2 represents a promising therapeutic target for ccRCC treatment.