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.
Project description:Lung cancer remains one of the most prevalent and lethal malignancies worldwide, with non-small cell lung cancer (NSCLC) representing the most common subtype—highlighting the critical need for novel therapeutic approaches. Here, we identify the retinoic acid receptor-related orphan receptor gamma (RORγ) as a key driver of NSCLC progression. Integrative bioinformatics and immunohistochemical analysis revealed that RORγ is highly expressed in NSCLC tissues and that its expression correlates with poor patient prognosis. Functionally, elevated RORγ significantly enhanced the proliferation, migration, and invasion capabilities of NSCLC cells. Conversely, treatment with the RORγ antagonist or genetic silencing of RORγ potently suppressed these malignant phenotypes both in vitro and in vivo. Mechanistically, RORγ directly binds to the promoter region of NGF, stimulates NGF gene transcription, and thereby promotes NSCLC progression. RORγ antagonists suppress NGF expression and inhibit its downstream signalling pathways, whereas exogenous NGF supplementation or overexpression of NGF notably reverses the inhibitory effects of RORγ antagonists on NSCLC cells. Taken together, these results establish RORγ as a critical regulator of NSCLC and a promising therapeutic target for NSCLC treatment.
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.
Project description:Peritoneal metastasis (PM) is diagnosed in almost half of patients with advanced gastric cancer (GCa) and has a very poor prognosis. However, the molecular mechanisms of PM in GCa remain poorly understood. Here, we show that the elevated expression of RAR-related orphan receptor gamma (RORγ) in GCa tumors is a key driver of PM. RORγ drives GCa progression and metastasis by assembling a transcriptional complex with HIF-1α that regulates the expression of HIF-1α targets via recruitment of RNA polymerase II and p300. Mechanistically, RORγ hijacks HIF-1α to disrupt the interaction between HIF-1α and PHD3, leading to decreased HIF-1α hydroxylation, ubiquitylation and increased HIF-1α accumulation, nuclear translocation, and transactivation. RORγ antagonists block tumor growth and PM in multiple xenograft GCa models, and they effectively sensitize GCa tumors to chemotherapy in mice. Thus, our study uncovers a mechanism of RORγ-driven PM and offers a potential therapeutic option against advanced GCa.
Project description:Peritoneal metastasis (PM) is diagnosed in almost half of patients with advanced gastric cancer (GCa) and has a very poor prognosis. However, the molecular mechanisms of PM in GCa remain poorly understood. Here, we show that the elevated expression of RAR-related orphan receptor gamma (RORγ) in GCa tumors is a key driver of PM. RORγ drives GCa progression and metastasis by assembling a transcriptional complex with HIF-1α that regulates the expression of HIF-1α targets via recruitment of RNA polymerase II and p300. Mechanistically, RORγ hijacks HIF-1α to disrupt the interaction between HIF-1α and PHD3, leading to decreased HIF-1α hydroxylation, ubiquitylation and increased HIF-1α accumulation, nuclear translocation, and transactivation. RORγ antagonists block tumor growth and PM in multiple xenograft GCa models, and they effectively sensitize GCa tumors to chemotherapy in mice. Thus, our study uncovers a mechanism of RORγ-driven PM and offers a potential therapeutic option against advanced GCa.
Project description:Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive malignancy with limited therapeutic options. Although targeted therapies like pemigatinib provide partial clinical benefits, acquired resistance remains a significant challenge. Through integrative bioinformatics analysis of public datasets and immunohistochemical validation, we identified the retinoid-related orphan receptor gamma (RORγ) as markedly upregulated in iCCA. Genetic silencing and pharmacological inhibition of RORγ (GSK805/XY101) suppressed proliferation, induced apoptosis in vitro, and significantly reduced xenograft tumor growth in vivo. Mechanistically, RORγ promoted fibroblast growth factor receptor 2 (FGFR2) signaling via two complementary mechanisms: direct transcriptional activation of FGFR2 and induction of fibroblast growth factor 1 (FGF1) expression and secretion, which in turn activated FGFR2. Inhibition of RORγ markedly decreased FGF1 levels in conditioned media, whereas exogenous FGF1 restored tumor growth. Notably, RORγ antagonists synergized with pemigatinib to overcome resistance in pemigatinib-refractory models. Collectively, these findings identify the RORγ-FGF1-FGFR2 axis as a critical oncogenic driver in iCCA and highlight RORγ inhibition as a promising therapeutic strategy to suppress tumor progression and enhance sensitivity to FGFR inhibitors.
Project description:Aging is a major risk factor for diabetic kidney disease (DKD), with both conditions exhibiting similar renal pathology. We identify the energy-sensing molecule Retinoic acid-related orphan receptor γ (RORγ) as significantly downregulated in diabetic and aged kidneys. Tubule-specific RORγ deficiency exacerbates kidney injury, whereas its overexpression protects. Mechanistically, RORγ stabilizes insulin-induced gene 1 (INSIG1) by upregulating the deubiquitinase YOD1 and enhancing AMPK activity via CAB39, which together promote INSIG1 phosphorylation and subsequent stabilization. Stabilized INSIG1 potently blocks the ER-to-Golgi transport and activation of SREBP2 (cholesterol synthesis) and STING (inflammatory signaling). In diabetes, RORγ itself is suppressed transcriptionally by CTCF and functionally by impaired AMPK/SIRT1 signaling, which hinders its activation. Importantly, administration of a RORγ agonist or RORγ-enriched exosomes effectively alleviates diabetic kidney injury. Thus, RORγ emerges as a key regulatory node that mitigates DKD and renal aging by co-regulating AMPK-mediated metabolic and STING-driven innate immune pathways through INSIG1 stabilization.
Project description:Osteosarcoma (OS) is the most common malignant bone tumor with a poor prognosis. The treatment strategy has remained virtually unchanged over the past 40 years. Here, we show that the nuclear receptor RORγ may serve as a potential therapeutic target in osteosarcoma. OS exhibits a hyperactivated OXPHOS program, which fuels the carbon source to promote tumor progression. We found that RORγ is overexpressed in OS tumors and is linked to hyperactivated OXPHOS. RORγ induces the expression of PGC-1β and physically interacts with it to activate the OXPHOS program by upregulating the expression of respiratory chain component genes. Knockdown or pharmacological inhibition of RORγ strongly inhibits OXPHOS activation, downregulates mitochondrial functions and increases ROS production, which results in OS cell apoptosis and ferroptosis. RORγ inverse agonists strongly suppressed OS tumor growth and progression in multiple cell-based xenograft models and in chemotherapy-resistant, patient-derived xenograft (PDX) models and sensitized OS tumors to chemotherapy without obvious toxicity in mice. Taken together, our results indicate that RORγ is a critical regulator of the OXPHOS program in OS and provide a potential therapeutic strategy for this deadly disease.
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.