TMET-15. SREBP-1 upregulates SOAT1 to promote tumor growth by preventing lipotoxicity

Rapidly growing tumors require a continuous supply of cholesterol, which is sustained by upregulating sterol regulatory element-binding protein 1 (SREBP-1), a master transcription factor that drives cholesterol uptake and biosynthesis. Unexpectedly, our current study revealed that sterol O-acyltransferase 1 (SOAT1), an enzyme that stores cholesterol in lipid droplets, is co-upregulated with SREBP-1 across multiple cancer types. Mechanistically, SREBP-1 directly binds to the SOAT1 promoter and transcriptionally activates its expression, leading to cholesterol storage. Genetic silencing of SOAT1, while preserving SREBP-1 activity, resulted in cholesterol accumulation and mitochondrial oxidative stress, markedly impairing the growth of patient-derived organoids and xenografts from lung cancer and glioblastoma, the most lethal brain tumor, and significantly extending mouse survival. These findings uncover a dual role for SREBP-1 in regulating both cholesterol acquisition and storge to maintain cholesterol homeostasis, avoiding lipotoxicity and sustaining tumor growth. Disrupting this balance by targeting SOAT1 in tumors with hyperactive SREBP-1 offers a promising therapeutic strategy.