HIF activation causes synthetic lethality between the VHL tumor suppressor and the EZH1 histone methyltransferase

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Inactivation of the von Hippel-Lindau tumor suppressor protein (pVHL) is a key event in clear cell renal cell carcinoma (ccRCC).
• pVHL loss activates hypoxia-inducible factor (HIF) signaling, impacting gene expression and chromatin regulation.
• Chromatin modifiers are frequently altered in ccRCC, suggesting epigenetic dysregulation.

Purpose of the Study:

• To investigate the epigenetic alterations in ccRCC associated with pVHL loss.
• To identify potential therapeutic vulnerabilities in pVHL-defective ccRCC cells.

Main Methods:

• Analysis of H3K27 acetylation and methylation patterns in ccRCC.
• Utilized short hairpin RNA (shRNA) library screening.
• Employed CRISPR/Cas9 gene editing and pharmacological inhibition.
• Assessed the role of EZH1 in pVHL-defective ccRCC cell survival.

Main Results:

• ccRCC exhibits increased H3K27 acetylation and reduced H3K27 methylation, driven by HIF-dependent demethylase activity.
• pVHL-defective ccRCC cells show a dependency on the H3K27 methyltransferase EZH1.
• Targeting EZH1 significantly impacted the survival of these cancer cells.

Conclusions:

• pVHL loss in ccRCC leads to specific epigenetic changes, including altered H3K27 methylation.
• The H3K27 methyltransferase EZH1 is crucial for the survival of pVHL-deficient ccRCC cells.
• Targeting EZH1 represents a promising therapeutic strategy for ccRCC.