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EZH2 cooperates with SREBP2 to establish the epigenomic, transcriptomic and metabolic programs for driving oncogenesis [CUT&Tag II]

ABSTRACT: Enhancer of Zeste Homolog 2 (EZH2) is recurrently overexpressed in cancers, correlating with adverse clinical outcomes. How exactly EZH2 overexpression contributes to tumorigenicity is far from clear. We here report an unexplored tumor-promoting axis involving the EZH2 association with SREBP2, a master regulator of lipid metabolism. EZH2 and SREBP2 act together to potentiate the expression of mevalonate pathway genes, thereby enhancing cholesterol biosynthesis to sustain aggressive tumor growth. The partially disordered transcriptional activation domains (tADs) of EZH2 and SREBP2 directly bind and recruit p300 to mediate the proto-oncogene activation. Additionally, we employed Proteolysis Targeting Chimeras (PROTACs) to block such a noncanonical function of EZH2 in cancer. Independent EZH2-targeting PROTACs degraded EZH2 and SREBP2 both and downregulated the SREBP2-associated gene-expression program, leading to inhibition of tumor growth. Altogether, this study unveils the existence of an EZH2:SREBP2 axis in cancers, which operates to sustain tumorigenesis via promoting cholesterol metabolism, paradigm-shifting the current understanding of EZH2’s oncogenic functions.

ORGANISM(S): Homo sapiens

PROVIDER: GSE324561 | GEO | 2026/08/09

REPOSITORIES: GEO

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EZH2 cooperates with SREBP2 to establish the epigenomic, transcriptomic and metabolic programs for driving oncogenesis [CUT&RUN II]

Project description:Enhancer of Zeste Homolog 2 (EZH2) is recurrently overexpressed in cancers, correlating with adverse clinical outcomes. How exactly EZH2 overexpression contributes to tumorigenicity is far from clear. We here report an unexplored tumor-promoting axis involving the EZH2 association with SREBP2, a master regulator of lipid metabolism. EZH2 and SREBP2 act together to potentiate the expression of mevalonate pathway genes, thereby enhancing cholesterol biosynthesis to sustain aggressive tumor growth. The partially disordered transcriptional activation domains (tADs) of EZH2 and SREBP2 directly bind and recruit p300 to mediate the proto-oncogene activation. Additionally, we employed Proteolysis Targeting Chimeras (PROTACs) to block such a noncanonical function of EZH2 in cancer. Independent EZH2-targeting PROTACs degraded EZH2 and SREBP2 both and downregulated the SREBP2-associated gene-expression program, leading to inhibition of tumor growth. Altogether, this study unveils the existence of an EZH2:SREBP2 axis in cancers, which operates to sustain tumorigenesis via promoting cholesterol metabolism, paradigm-shifting the current understanding of EZH2’s oncogenic functions.

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Project description:An EZH2—SREBP2 axis promotes cholesterol biosynthesis and represents a noncanonical vulnerability in tumorigenesis

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