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

• Published in: Oncogene 2024-01, Vol.43 (4), p.281-293
• Main Authors: Erkner, Estelle, Hentrich, Thomas, Schairer, Rebekka, Fitzel, Rahel, Secker-Grob, Kathy-Ann, Jeong, Johan, Keppeler, Hildegard, Korkmaz, Fulya, Schulze-Hentrich, Julia M., Lengerke, Claudia, Schneidawind, Dominik, Schneidawind, Corina
• Format: Article
• Language: English
• Subjects: 13/2; 38/91; 631/67/1990/283; 631/67/2327; 82/80; 96/95; Apoptosis; Atorvastatin; Cell Biology; Cell cycle; Cell death; Cholesterol; Cholesterol - metabolism; Cytarabine; Down-regulation; Feedback; Homeostasis; Human Genetics; Humans; Internal Medicine; Leukemia; Leukemia - drug therapy; Leukemia - genetics; Lipid metabolism; Medicine; Medicine & Public Health; Metabolism; Neoplasms; Oncology; Regulatory sequences; Retinoic acid receptors; Statins; Sterol Regulatory Element Binding Protein 2 - genetics; Sterol Regulatory Element Binding Protein 2 - metabolism; Therapeutic targets; Transcription factors; Tumorigenesis
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-023-02903-3

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.