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; Hong Wu Chen

doi:10.1038/s41467-019-12529-3

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 journal › Article › peer-review

119 Citations (Scopus)

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 language	English
Article number	4621
Journal	Nature Communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-12529-3
Publication status	Published - Dec 1 2019
Externally published	Yes

ASJC Scopus subject areas

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41467-019-12529-3

Cite this

Cai, D., Wang, J., Gao, B., Li, J., Wu, F., Zou, J. X., Xu, J., Jiang, Y., Zou, H., Huang, Z., Borowsky, A. D., Bold, R. J., Lara, P. N., Li, J. J., Chen, X., Lam, K. S., To, K. F., Kung, H. J., Fiehn, O., ... Chen, H. W. (2019). RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype. Nature Communications, 10(1), Article 4621. https://doi.org/10.1038/s41467-019-12529-3

Cai, 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 2019, 'RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype', Nature Communications, vol. 10, no. 1, 4621. https://doi.org/10.1038/s41467-019-12529-3

@article{fd45dfae9ca842cb8b3d739c0bea7f9a,

title = "RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s).",

year = "2019",

month = dec,

day = "1",

doi = "10.1038/s41467-019-12529-3",

language = "English",

volume = "10",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

TY - JOUR

T1 - RORγ is a targetable master regulator of cholesterol biosynthesis in a cancer subtype

AU - Cai, Demin

AU - Wang, Junjian

AU - Gao, Bei

AU - Li, Jin

AU - Wu, Feng

AU - Zou, June X.

AU - Xu, Jianzhen

AU - Jiang, Yuqian

AU - Zou, Hongye

AU - Huang, Zenghong

AU - Borowsky, Alexander D.

AU - Bold, Richard J.

AU - Lara, Primo N.

AU - Li, Jian Jian

AU - Chen, Xinbin

AU - Lam, Kit S.

AU - To, Ka Fai

AU - Kung, Hsing Jien

AU - Fiehn, Oliver

AU - Zhao, Ruqian

AU - Evans, Ronald M.

AU - Chen, Hong Wu

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85073168303&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85073168303&partnerID=8YFLogxK

U2 - 10.1038/s41467-019-12529-3

DO - 10.1038/s41467-019-12529-3

M3 - Article

C2 - 31604910

AN - SCOPUS:85073168303

SN - 2041-1723

VL - 10

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 4621

ER -

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

Abstract

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this