Arginine Promotes Metabolic Reprogramming and Liver Tumorigenesis

A common hallmark of cancer is the rewiring of cellular metabolism, including amino acid metabolism, to promote cell proliferation. However, the upstream mechanisms and downstream targets of this metabolic reprogramming are not well understood. Mossmann and colleagues sought to determine these mechanisms and their effects on tumorigenicity and showed elevated arginine levels in both murine and human hepatocellular carcinoma (HCC) despite downregulation of arginine synthesis. Increased arginine uptake compensates for downregulation of arginine synthesis and is critical for liver tumor development. Moreover, arginine-to-polyamine conversion is reduced due to decreased arginase 1 (ARG1) and agmatinase (AGMAT) expression, which, in turn, preserves the high levels of unmetabolized arginine needed for liver tumorigenesis. High arginine levels determined the expression of metabolic genes, indicating that arginine controls oncogenic metabolism at the transcriptional level. Asparagine synthetase (ASNS) was one of the metabolic genes most activated by arginine. ASNS was found to promote HCC, at least in part, by further enhancing arginine uptake, creating a positive feedback loop. Further evaluation of the effects of high arginine levels on transcriptional metabolic reprogramming revealed that arginine specifically binds to the N-terminal region of RBM39 to control metabolic gene expression. RBM39 expression is elevated in murine liver tumors, and depletion of RBM39 reduced tumor burden. These results also translated to human HCC, as ARG1 and AGMAT expression was decreased, while RBM39 and ASNS expression was increased, in patient samples of HCC. Additionally, treatment of 20 patient-derived HCC organoids with indisulam, an aryl sulfonamide that depletes RBM39, reduced tumor growth in a dose-dependent manner, supporting depletion of RBM39 as a therapeutic option in HCC. In summary, the results of this study show that arginine levels are increased in HCC to promote metabolic reprogramming and tumorigenicity. Furthermore, the study suggests that targeting this arginine–RBM39 dependence in HCC could serve as a potential therapeutic option.

Mossmann D, Müller C, Park S, Ryback B, Colombi M, Ritter N, et al. Arginine reprograms metabolism in liver cancer via RBM39. Cell 2023;186:5068–83.e23.

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