Mutant p53-R280K hijacks SREBP1 to promote fatty acid synthesis and breast cancer progression via FASN.

backgroundLipid metabolic reprogramming is a hallmark of cancer, in which fatty acid synthesis is crucial for the rapid proliferation and metastasis of cancer cells. The p53-R280K mutation drives aggressive cancer, yet its role in fatty acid synthesis remains unclear.

methodsThe CRISPR/CasRx technique was applied to knockdown endogenous mutant p53-R280K in MDA-MB-231 cells and wild-type p53 (WT-p53) in ZR75-1 cells. Luciferase reporter and ChIP assays demonstrated mutant p53-R280K binding to the FASN promoter and regulating its activity. Oil red O staining, flow cytometry, and triglyceride assays were used to determine the levels of lipid synthesis. Cell proliferation, wound healing and cell invasion assays were performed to detect the malignant phenotypes in vitro. Subcutaneous tumorigenesis and lung metastasis models of nude mice were established to validate tumor growth and metastasis in vivo.

resultsIn this study, we reveal that p53-R280K hijacks the lipogenic transcription factor SREBP1 to form a transcriptional co-activation complex. This complex binds to and activates the fatty acid synthase (FASN) promoter, upregulating FASN expression. Enhanced FASN activity fuels de novo fatty acid synthesis, increasing lipid accumulation in breast cancer cells. Crucially, p53-R280K promotes cell proliferation, migration, and invasion in vitro, and drives tumor growth and lung metastasis in vivo in a FASN-dependent manner, as genetic or pharmacological inhibition of FASN abolishes these oncogenic effects.

conclusionThese findings establish that p53-R280K acquires a gain-of-function by co-opting SREBP1 to activate FASN transcription, reprogramming lipid metabolism to fuel breast cancer progression. Targeting the p53-R280K/SREBP1/FASN axis presents a promising therapeutic strategy for cancers harboring this specific p53 mutation.