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 Zhao, Ronald M. Evans and Hong-Wu Chen ()
Additional contact information
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
Primo N. Lara: University of California Davis
Jian Jian Li: University of California Davis
Xinbin Chen: University of California Davis
Kit S. Lam: University of California Davis
Ka-Fai To: The Chinese University of Hong Kong
Hsing-Jien Kung: University of California Davis
Oliver Fiehn: University of California Davis
Ruqian Zhao: Nanjing Agricultural University
Ronald M. Evans: Howard Hughes Medical Institute, Salk Institute
Hong-Wu Chen: University of California Davis

Nature Communications, 2019, vol. 10, issue 1, 1-17

Abstract: 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.

Date: 2019
References: Add references at CitEc
Citations: View citations in EconPapers (1)

Downloads: (external link)
https://www.nature.com/articles/s41467-019-12529-3 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12529-3

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-019-12529-3

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().