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

Enhancer of zeste homolog 2 (EZH2) is frequently overexpressed in cancer, correlating with adverse clinical outcomes. However, how EZH2 overexpression supports tumorigenicity is not fully elucidated. Here we identify a previously unexplored tumour-promoting axis involving EZH2-SREBP2 association. EZH2 and SREBP2, a master regulator of lipid metabolism, cooperate to drive high expression of mevalonate pathway genes, enhancing cholesterol biosynthesis and sustaining tumour growth. Transcriptional activation domains of EZH2 and SREBP2 bind p300 directly, mediating proto-oncogene activation. Furthermore, we employed proteolysis targeting chimeras (PROTACs) to target this non-canonical EZH2 function. Independent EZH2-targeting PROTACs degrade both EZH2 and SREBP2, downregulating SREBP2-associated gene-expression programmes and inhibiting tumour growth. Collectively, this study unveils an EZH2-SREBP2 regulatory axis that promotes cholesterol biosynthesis and fuels tumorigenesis, shifting the current paradigm of EZH2's oncogenic functions.