Arginine reprograms metabolism in liver cancer via RBM39

Area of Science:

• Oncology
• Metabolic pathways
• Cancer biology

Background:

• Metabolic reprogramming is a key characteristic of cancer, but the underlying mechanisms and their role in tumorigenicity are not fully understood.
• Altered cellular metabolism significantly contributes to cancer development and progression.

Purpose of the Study:

• To investigate the role of arginine metabolism in hepatocellular carcinoma (HCC) development.
• To elucidate the mechanisms by which altered arginine levels promote tumorigenicity.

Main Methods:

• Analysis of arginine levels in murine and patient HCC samples.
• Investigation of arginine uptake and conversion pathways.
• Assessment of the impact of arginine on global metabolic reprogramming.
• Identification of molecular targets, including RNA-binding motif protein 39 (RBM39), involved in arginine-mediated metabolic control.

Main Results:

• Arginine levels are elevated in HCC despite reduced synthesis, due to increased uptake and decreased conversion to polyamines.
• High arginine levels drive metabolic reprogramming across glucose, amino acid, nucleotide, and fatty acid pathways.
• Arginine binds to RBM39, regulating metabolic gene expression.
• RBM39 upregulates asparagine synthesis, enhancing arginine uptake and creating a positive feedback loop.

Conclusions:

• Arginine acts as a critical signaling molecule in HCC, reprogramming cellular metabolism to promote tumor growth.
• The arginine-RBM39-asparagine axis represents a novel mechanism sustaining oncogenic metabolism in HCC.
• Targeting arginine metabolism could offer new therapeutic strategies for HCC.