An EZH2-SREBP2 axis promotes cholesterol biosynthesis and represents a noncanonical vulnerability in tumorigenesis.

EZH2 and SREBP2 form a regulatory axis that promotes cholesterol biosynthesis and supports tumor growth, with EZH2-targeting PROTACs degrading both proteins to inhibit tumors.

• Why it matters: Understanding how EZH2 overexpression supports tumorigenicity is crucial because EZH2 is frequently overexpressed in cancer and linked to poor clinical outcomes. This knowledge could reveal new therapeutic targets.
• What they did: The study identified an EZH2-SREBP2 association that drives high expression of mevalonate pathway genes, enhancing cholesterol biosynthesis. Researchers used proteolysis targeting chimeras (PROTACs) to degrade EZH2 and SREBP2, reducing gene expression and tumor growth.
• The result: Targeting this axis with PROTACs downregulates SREBP2-related gene programs and inhibits tumor growth, unveiling a noncanonical EZH2 function that could be exploited for cancer therapy.