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

研究成果: 雜誌貢獻文章同行評審

38 引文 斯高帕斯(Scopus)

摘要

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.

原文英語
文章編號4621
期刊Nature Communications
10
發行號1
DOIs
出版狀態已發佈 - 12月 1 2019
對外發佈

ASJC Scopus subject areas

  • 化學 (全部)
  • 生物化學、遺傳與分子生物學 (全部)
  • 物理與天文學 (全部)

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