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RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

Author

Listed:
  • Demin Cai

    (University of California Davis)

  • Junjian Wang

    (University of California Davis)

  • Bei Gao

    (University of California Davis)

  • Jin Li

    (University of California Davis)

  • Feng Wu

    (The Chinese University of Hong Kong)

  • June X. Zou

    (University of California Davis)

  • Jianzhen Xu

    (Shantou University Medical College)

  • Yuqian Jiang

    (University of California Davis)

  • Hongye Zou

    (University of California Davis)

  • Zenghong Huang

    (University of California Davis)

  • Alexander D. Borowsky

    (University of California Davis)

  • Richard J. Bold

    (University of California Davis
    University of California Davis)

  • Primo N. Lara

    (University of California Davis)

  • Jian Jian Li

    (University of California Davis)

  • Xinbin Chen

    (University of California Davis
    University of California Davis)

  • Kit S. Lam

    (University of California Davis
    University of California Davis)

  • Ka-Fai To

    (The Chinese University of Hong Kong)

  • Hsing-Jien Kung

    (University of California Davis
    University of California Davis)

  • Oliver Fiehn

    (University of California Davis)

  • Ruqian Zhao

    (Nanjing Agricultural University
    Nanjing Agricultural University)

  • Ronald M. Evans

    (Howard Hughes Medical Institute, Salk Institute)

  • Hong-Wu Chen

    (University of California Davis
    University of California Davis)

Abstract

Tumor subtype-specific metabolic reprogrammers could serve as targets of therapeutic intervention. Here we show that triple-negative breast cancer (TNBC) exhibits a hyper-activated cholesterol-biosynthesis program that is strongly linked to nuclear receptor RORγ, compared to estrogen receptor-positive breast cancer. Genetic and pharmacological inhibition of RORγ reduces tumor cholesterol content and synthesis rate while preserving host cholesterol homeostasis. We demonstrate that RORγ functions as an essential activator of the entire cholesterol-biosynthesis program, dominating SREBP2 via its binding to cholesterol-biosynthesis genes and its facilitation of the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces chromatin acetylation at cholesterol-biosynthesis gene loci. RORγ antagonists cause tumor regression in patient-derived xenografts and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our study uncovers a master regulator of the cholesterol-biosynthesis program and an attractive target for TNBC.

Suggested Citation

  • Demin Cai & Junjian Wang & Bei Gao & Jin Li & Feng Wu & June X. Zou & Jianzhen Xu & Yuqian Jiang & Hongye Zou & Zenghong Huang & Alexander D. Borowsky & Richard J. Bold & Primo N. Lara & Jian Jian Li , 2019. "RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype," Nature Communications, Nature, vol. 10(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12529-3
    DOI: 10.1038/s41467-019-12529-3
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