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

  • Nat Cell Biol. 2026 Aug 14:10.1038/s41556-026-02048-x. doi: 10.1038/s41556-026-02048-x.
Arum Kim  1 ,  Bo Pan  1  2 ,  Xufen Yu  3  4  5 ,  Xing Gao  3  4 ,  Nelli Khudaverdyan  6 ,  Fatemeh Taherian  7  8 ,  Chenxi Xu  1  2 ,  Haiqing Zhong  1 ,  Yan Xiong  3  4 ,  H Ümit Kaniskan  3  4 ,  Masoud Vedadi  7  8 ,  Jikui Song  6 ,  Jian Jin  3  4 ,  Ling Cai  9  10 ,  Gang Greg Wang  11  12  13  14
Affiliations
  • 1. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA.
  • 2. Department of Pathology, Duke University School of Medicine, Durham, NC, USA.
  • 3. Departments of Pharmacological Sciences and Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 4. Mount Sinai Center for Therapeutics Discovery, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
  • 5. Fudan University School of Pharmacy, Shanghai, China.
  • 6. Department of Biochemistry, University of California, Riverside, CA, USA.
  • 7. Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada.
  • 8. Drug Discovery Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
  • 9. Department of Pathology, Duke University School of Medicine, Durham, NC, USA. [email protected].
  • 10. Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA. [email protected].
  • 11. Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, USA. [email protected].
  • 12. Department of Pathology, Duke University School of Medicine, Durham, NC, USA. [email protected].
  • 13. Duke Cancer Institute, Duke University School of Medicine, Durham, NC, USA. [email protected].
  • 14. Lineberger Comprehensive Cancer Center, Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. [email protected].
PMID: 42601451 DOI: 10.1038/s41556-026-02048-x
Abstract

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.

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