RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype
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AbstractTumor 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.
All Author(s) ListCai D, Wang J, Gao B, Li J, Wu F, Zou JX, Xu J, Jiang Y, Zou H, Huang Z, Borowsky AD, Bold RJ, Lara PN, Li JJ, Chen X, Lam KS, To KF, Kung HJ, Fiehn O, Zhao R, Evans RM, Chen HW
Journal nameNature Communications
Volume Number10
Issue Number1
PublisherNature Publishing Group
Article number4621
LanguagesEnglish-United Kingdom

Last updated on 2020-17-09 at 00:36