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Targeting EZH2-driven cholesterol metabolic vulnerability through Napabucasin suppresses ovarian cancer metastasis

Mingjun Ma1, Chao Wang1, Yue Zhang1

  • 1Department of Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Clinical and Translational Research Center, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, China.

Cell Death & Disease
|June 29, 2026
PubMed

Insights

Enhancer of Zeste Homolog 2 (EZH2) drives ovarian cancer metastasis by altering cholesterol metabolism. Targeting the EZH2/Rap1A axis with Napabucasin shows promise for treating this lethal gynecologic malignancy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Metabolism

Background:

  • Ovarian cancer is a lethal gynecologic malignancy, with metastasis causing most deaths.
  • EZH2 overexpression is linked to cancer progression and metastasis via metabolic dysregulation.
  • The precise role of EZH2 in reprogramming cholesterol metabolism for ovarian cancer metastasis is unclear.

Purpose of the Study:

  • To investigate the mechanism by which EZH2 promotes ovarian cancer metastasis through cholesterol metabolism.
  • To evaluate Napabucasin as a therapeutic agent targeting the EZH2 pathway in ovarian cancer.

Main Methods:

  • Assessed EZH2 expression in ovarian cancer tissues.
  • Utilized genetic silencing of EZH2 to study its effects on tumor growth and metastasis.
  • Investigated the NF-κB-Rap1A signaling axis and cholesterol metabolism regulators (SREBP2, TMED10).
  • Tested Napabucasin's efficacy in vitro and in vivo.

Main Results:

  • EZH2 is highly expressed in ovarian cancer, correlating with poor prognosis.
  • EZH2 silencing reduced tumor proliferation and metastasis.
  • EZH2 activates NF-κB-Rap1A and reprograms cholesterol metabolism by upregulating SREBP2 and downregulating TMED10.
  • Napabucasin inhibited the EZH2/Rap1A axis, altered cholesterol metabolism, and suppressed metastasis in vivo.

Conclusions:

  • EZH2 promotes ovarian cancer metastasis by rewiring cholesterol metabolism via the NF-κB-Rap1A/SREBP2/TMED10 pathway.
  • Napabucasin effectively inhibits EZH2-driven metastasis and represents a potential therapeutic strategy for ovarian cancer.

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