Cdk5 regulates glutamine metabolism in colorectal cancer via the EZH2-GLS1 axis

Colorectal cancer (CRC) is a globally prevalent malignancy that poses a substantial threat to human health. Despite advancements in prevention, diagnosis, and treatment, CRC remains a formidable clinical challenge due to the incomplete elucidation of its pathological mechanisms. Glutamine, an abundant amino acid, exerts pivotal roles in energy production, redox homeostasis, macromolecular biosynthesis, and signal transduction within cancer cells. Elucidating the role of glutamine in CRC pathogenesis is therefore of profound significance. In this study, we investigated the regulatory role of Cyclin-dependent kinase 5 (Cdk5) in glutamine metabolism in CRC, employing both human CRC cell models and murine models. Our findings demonstrated that Cdk5 knockdown accelerated glutamine uptake while suppressing the proliferation of CRC cells. Further exploration of the underlying molecular mechanisms revealed that Cdk5 physically interacts with EZH2. Besides, Cdk5 phosphorylates EZH2 at specific sites, and then the PRC2 complex (centered around EZH2) catalyzes the production of H3K27me3, an inhibitory marker, to regulate the expression of genes involved in glutamine metabolism. At the same time, we also found that modulation of the Cdk5-EZH2 axis alters the epigenetic landscape of genes associated with glutamine transporters and tricarboxylic acid cycle (TCA) enzymes, resulting in reduced mitochondrial activity, impaired glutamine utilization in the TCA cycle, and decreased ATP production-collectively impacting the global glutamine metabolic processes in CRC cells. In in vivo experiments utilizing a murine CRC model, we established five experimental groups. Results showed that Dinaciclib treatment suppressed tumor growth in the CRC model, with this inhibitory effect being further potentiated upon combination with glutamine deprivation. These findings not only uncover the intricate interplay between Cdk5, EZH2, and glutamine metabolism in CRC but also offer novel insights into the pathogenic mechanisms of CRC and identify potential therapeutic targets.