DDX39B facilitates the malignant progression of hepatocellular carcinoma via activation of SREBP1- mediated de novo lipid synthesis

Abstract Purpose The detailed molecular mechanisms of aberrant lipid metabolism in HCC remains unclear. Herein, we focused on the potential role of DDX39B in aberrant lipogenesis and malignant development in HCC. Methods DDX39B expression in HCC and para-cancer tissues was measured by immunohistochemistry. CCK-8, clone formation and transwell assays were utilized to detect HCC cells proliferation, migration and invasion in virto . Oil red O, nile red staining, triglyceride and cholesterol detections were used to measure lipogenesis. Co-immunoprecipitation was used to detect interactions between DDX39B and SREBP1. Fractionation and immunofluorescence assays were performed to investigate the impact of DDX39B on SREBP1 nuclear translocation. Luciferase assay was used to explore transcriptional activity of SREBP1. Nude mice subcutaneous and orthotopic xenograft models were performed to verify the contribution of DDX39B/SREBP1 axis in tumor growth, lung metastasis and lipid synthesis in vivo. Results DDX39B is upregulated in HCC tissues and predicts worse prognosis. Upregulated DDX39B contributes to the proliferation, metastasis and lipogenesis of HCC cells. Mechanistically, DDX39B directly interacts with SREBP1 and silencing DDX39B impairs the stabilization of the SREBP1 protein through FBXW7-mediated ubiquitination and degradation of SREBP1. Furthermore, DDX39B deficiency decreases the nuclear translocation and activation of SREBP1 and transcription of SREBP1 downstream genes, resulting in reduced lipid accumulation. Conclusions Our study reveals a novel mechanism by which DDX39B facilitates the malignant progression of HCC via activation of SREBP1-mediated de novo lipogenesis, implicating DDX39B as both a potential predictor of recurrence and prognosis and a promising therapeutic target.