A Multi-omics PTM Atlas Reveals Key Insights into Metabolic Reprogramming in Colorectal Cancer

Colorectal cancer (CRC) is a leading cause of cancer-related mortality worldwide, with limited effective targeted therapies. Metabolic reprogramming is a hallmark of cancer, and post-translational modifications (PTMs), such as phosphorylation, ubiquitination, and malonylation, play critical roles in regulating metabolic pathways. However, their contribution to metabolic reprogramming in CRC remains unclear.

Phosphorylation, ubiquitination, and malonylation were analyzed in paired CRC and adjacent normal tissues using high-resolution mass spectrometry. Differential PTM patterns were analyzed, followed by identification of key regulatory enzymes and modification sites. Functional enrichment, protein-protein interaction (PPI) networks, and multi-omics integration were used to explore PTMs' role in CRC metabolism.

We identified 59 differential phosphorylation sites, 263 ubiquitination sites, and 64 malonylation sites in CRC tissues compared with normal tissues, affecting key metabolic enzymes such as IDH1, LDHA, PDHA1, and GAPDH. Altered ubiquitination of IDH1 and LDHA may be associated with changes in protein stability and activity. Phosphorylation of PDHA1 correlated with its modified levels, potentially promoting glycolytic preference in CRC, while increased malonylation of GAPDH may influence its enzymatic activity and glycolytic flux. Protein interaction and pathway analyses further revealed a PTM-regulated metabolic network, suggesting a potential role of PTMs in CRC metabolic reprogramming.

This study suggests that PTMs may contribute to metabolic reprogramming in CRC by modulating key metabolic enzymes, including IDH1, LDHA, PDHA1, and GAPDH. These modifications may influence glycolysis and energy metabolism, highlighting PTM-regulated pathways as potential therapeutic targets. The integrated PTM atlas offers insights into the metabolic landscape of CRC.