Arginine reprograms metabolism in liver cancer via RBM39 [AA_overexpression/RBM39depletion]

Metabolic reprogramming is a hallmark of cancer. However, mechanisms underlying metabolic reprogramming and how altered metabolism in turn enhances tumorigenicity are poorly understood. Here, we report that arginine levels are elevated in hepatocellular carcinoma (HCC) despite reduced expression of arginine synthesis genes, in murine and patient tumors. Tumor cells accumulate high levels of arginine due to increased uptake and reduced arginine-to-polyamine conversion. Importantly, the high levels of arginine promote tumor formation via further metabolic reprogramming, including changes in glucose, amino acid, nucleotide, and fatty acid metabolism. Mechanistically, arginine binds RNA-binding motif protein 39 (RBM39) to control expression of metabolic genes. RBM39-mediated upregulation of asparagine synthesis leads to enhanced arginine uptake, creating a positive feedback loop to sustain high arginine levels and oncogenic metabolism. Thus, arginine is a second messenger-like molecule that reprograms metabolism to promote tumor growth. As part of this study we performed gene expression profiling analysis using data obtained from [1] RNA-seq of SNU-449 cells stably overexpressing arginase1 (ARG1) and agmatinase (AGMAT).These data we compared to control cells (SNU-449 infected with empty vector). [2] RNA-seq of SNU-449 cells treated with indisulam combined with RBM39 siRNA.These data we compared to control cells (SNU-499 treated with DMSO combinded with non-targeting siRNA). Please note that processed data was generated with two different analysis pipelines; [1] differential splicing and intron retention analysis data (*ASEs_contrasts_20230307.xlsx) [2] conventional differential expression analysis (*contrasts_20230307.xlsx)