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

Authors: Cai, Demin; Wang, Junjian; Gao, Bei; Li, Jin; Wu, Feng; Zou, June X; Xu, Jianzhen; Jiang, Yuqian; Zou, Hongye; Huang, Zenghong; Borowsky, Alexander D; Bold, Richard J; Lara, Primo N; Li, Jian Jian; Chen, Xinbin; Lam, Kit S; To, Ka-Fai; Kung, Hsing-Jien; Fiehn, Oliver; Zhao, Ruqian; Evans, Ronald M; Chen, Hong-Wu

Published In Nat Commun, (2019 10 11)

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.

PubMed ID: 31604910 Exiting the NIEHS site

MeSH Terms: Acetylation; Animals; Cell Line, Tumor; Cholesterol/biosynthesis*; Chromatin/metabolism; Homeostasis/drug effects; Humans; MCF-7 Cells; Metabolic Networks and Pathways; Metabolomics; Mice; Mice, Inbred BALB C; Nuclear Receptor Subfamily 1, Group F, Member 3/antagonists & inhibitors; Nuclear Receptor Subfamily 1, Group F, Member 3/physiology*; Sterol Regulatory Element Binding Protein 2/metabolism*; Triple Negative Breast Neoplasms/metabolism*

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