RBM45 reprograms lipid metabolism promoting hepatocellular carcinoma via Rictor and ACSL1/ACSL4

作者：Chun Wang, Zhihang Chen, Yun Yi, Yang Ding, Fei Xu, Hui Kang, Kun Lin, Xiawen Shu, Zibiao Zhong, Zhonglin Zhang, Jing Liu, Zhong Xu, Lan Liu, Xingxing He, Ying Chang, Qiu Zhao · 发表于：Oncogene · 年份：2023 · DOI：10.1038/s41388-023-02902-4 · 被引用次数：38 · 研究领域：Cancer, Lipids, and Metabolism、RNA modifications and cancer、Cancer, Hypoxia, and Metabolism

Reprogramming of lipid metabolism during hepatocarcinogenesis is not well elucidated. Here, we aimed to explore pivotal RNA-binding motif proteins (RBMs) in lipid metabolism and their therapeutic potential in hepatocellular carcinoma (HCC). Through bioinformatic analysis, we identified RBM45 as a critical gene of interest among differentially expressed RBMs in HCC, with significant prognostic relevance. RBM45 influenced the malignant biological phenotype and lipid metabolism of HCC cells. Mechanically, RBM45 promotes de novo lipogenesis in HCC by directly targeting two key enzymes involved in long-chain fatty acid synthesis, ACSL1 and ACSL4. RBM45 also targets Rictor, which has been demonstrated to modulate lipid metabolism profoundly. RBM45 also aided lipid degradation through activating a key fatty acid β oxidation enzyme, CPT1A. Thus, RBM45 boosted lipid synthesis and decomposition, indicating an enhanced utility of lipid fuels in HCC. Clinically, body mass index was positively correlated with RBM45 in human HCCs. The combination of a PI3K/AKT/mTOR pathway inhibitor in vitro or Sorafenib in orthotopic liver cancer mouse models with shRBM45 has a more significant therapeutic effect on liver cancer than the drug alone. In summary, our findings highlight the versatile roles of RBM45 in lipid metabolism reprogramming and its therapeutic potential in HCC. Lipids induced RBM45 expression. In turn, RBM45 promoted the utility of lipid in HCCs through accelerating both de novo lipo...