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Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer

ABSTRACT: Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer

PROVIDER: PRJNA545129 | ENA |

REPOSITORIES: ENA

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Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer [RNA-Seq]

Project description:We show that triple-negative breast cancer (TNBC) exhibits a hyper-activated MVA-CB 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 contents and synthesis rate while preserving host cholesterol homeostasis. We demonstrate, for the first time, that RORγ functions as a master activator of the entire MVA-CB program, dominantly over SREBP2, through its own direct binding and facilitating the recruitment of SREBP2. RORγ inhibition disrupts its association with SREBP2 and reduces MVA-CB chromatin acetylation. RORγ antagonists cause sustained TNBC tumor regression in patient-derived and immune-intact models. Their combination with cholesterol-lowering statins elicits superior anti-tumor synergy selectively in TNBC. Together, our studies uncover a previously unsuspected master regulator of MVA-CB and an attractive target for TNBC.

2019-08-04 | GSE131856 | GEO

Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer [ChIP-Seq]

2019-08-04 | GSE126380 | GEO

Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer [ChIP-Seq]

Project description:Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer [ChIP-Seq]

| PRJNA521745 | ENA

Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer [RNA-Seq]

Project description:Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer [RNA-Seq]

| PRJNA545131 | ENA

ChIP-seq genome-wide maps of nuclear receptor RORγ chromatin state in the liver of pig exposed to mycotoxin

Project description:We show that RORγ functions as a master activator of the entire mevalonate pathway-cholesterol biosynthesis program in the porcine liver. RORγ genome-wide binding enrichments in the liver were significantly reduced in response to mycotoxin exposure.

2024-02-01 | GSE166520 | GEO

The RORɣ/SREBP2 pathway is a master regulator of cholesterol metabolism and serves as potential therapeutic target in t(4;11) leukemia

Project description:Dysregulated cholesterol homeostasis promotes tumorigenesis and progression. Therefore, metabolic reprogramming constitutes a new hallmark of cancer. However, until today, only few therapeutic approaches exist to target this pathway due to the often-observed negative feedback induced by agents like statins leading to controversially increased cholesterol synthesis upon inhibition. Sterol regulatory element-binding proteins (SREBPs) are key transcription factors regulating the synthesis of cholesterol and fatty acids. Since SREBP2 is difficult to target, we performed pharmacological inhibition of retinoic acid receptor (RAR)-related orphan receptor gamma (RORγ), which acts upstream of SREBP2 and serves as master regulator of the cholesterol metabolism. This resulted in an inactivated cholesterol-related gene program with significant downregulation of cholesterol biosynthesis. Strikingly, these effects were more pronounced than the effects of fatostatin, a direct SREBP2 inhibitor. Upon RORγ inhibition, RNA sequencing showed strongly increased cholesterol efflux genes leading to leukemic cell death and cell cycle changes in a dose- and time-dependent manner. Combinatorial treatment of t(4;11) cells with the RORγ inhibitor showed additive effects with cytarabine and even strong anti-leukemia synergism with atorvastatin by circumventing the statin-induced feedback. Our results suggest a novel therapeutic strategy to inhibit tumor-specific cholesterol metabolism for the treatment of t(4;11) leukemia.

2024-01-01 | GSE242401 | GEO

Nuclear receptor RORγ is a targetable master regulator of cholesterol in a subtype of breast cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2019-08-04 | GSE131857 | GEO

ROR? is a targetable master regulator of cholesterol biosynthesis in a cancer subtype.

Project description: Not available

| S-EPMC6789042 | biostudies-literature

Natural compounds ursolic acid and digoxin exhibit inhibitory activities to cancer cells in RORγ-dependent and -independent manner

Project description:Natural compounds ursolic acid (UA) and digoxin isolated from fruits and other plants display potent anti-cancer effects in preclinical studies. UA and digoxin have been at clinical trials for treatment of different cancers including prostate cancer, pancreatic cancer and breast cancer. However, they displayed limited benefit to patients. Currently, a poor understanding of their direct targets and mechanisms of action (MOA) severely hinders their further development. We previously identified nuclear receptor RORγ as a novel therapeutic target for castration-resistant prostate cancer (CRPC) and triple-negative breast cancer (TNBC) and demonstrated that tumor cell RORγ directly activates gene programs such as androgen receptor (AR) signaling and cholesterol metabolism. Previous studies also demonstrated that UA and digoxin are potential RORγt antagonists in modulating the functions of immune cells such as Th17 cells. Here we showed that UA displays a strong activity in inhibition of RORγ-dependent transactivation function in cancer cells, while digoxin exhibits no effect at clinically relevant concentrations. In prostate cancer cells, UA down-regulates RORγ-stimulated AR expression and AR signaling, whereas digoxin up-regulates AR signaling pathway. In TNBC cells, UA but not digoxin alters RORγ-controlled gene programs of cell proliferation, apoptosis and cholesterol-biosynthesis.Together, our study reveals for the first-time that UA, but not digoxin, acts as a natural antagonist of RORγ in the cancer cells. Our finding that RORγ is a direct target of UA in cancer cells will help select patients with tumors that likely respond to UA treatment.

2023-05-17 | GSE230039 | GEO

RORγ modulates the extracellular matrix to facilitate hepatocellular carcinoma growth and metastasis

Project description:Approximately 80%-90% of hepatocellular carcinomas (HCC) occur in a premalignant environment of fibrosis and abnormal extracellular matrix (ECM), predicting an essential role of abnormal matrix in the tumorigenesis and progress of HCC. However, the determinants of ECM in HCC are poorly defined. Here, we show that nuclear receptor RORγ is highly expressed and amplified in HCC tumors. RORγ functions as an essential activator of the matrisome program via directly driving the expression of major ECM genes in HCC cells. The elevated RORγ increased Fibronectin-1 deposition, cell-matrix adhesion, collagen production and cross-linkling, creating a favorable microenvironment to boost liver cancer metastasis. Moreover, RORγ antagonists effectively inhibit tumor growth and metastasis via ECM remodeling in multiple HCC xenografts and immune-intact models, and they effectively sensitize HCC tumors to sorafenib therapy in mice. Notably, the elevated RORγ expression is associated with ECM remodeling and metastasis in patients with HCC. Taken together, we identify RORγ as a key player in HCC progression by remodeling ECM and as an attractive therapeutic target for advanced HCC.

2024-01-24 | GSE234660 | GEO

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