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

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, Xinbin Chen, Kit S. Lam, Ka Fai To, Hsing Jien Kung, Oliver Fiehn, Ruqian ZhaoRonald M. Evans, Hong Wu Chen

Research output: Contribution to journalArticle

7 Scopus citations

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.

Original languageEnglish (US)
Article number4621
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

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