Rewiring Lysine Catabolism in Cancer Leads to Increased Histone Crotonylation and Immune Escape

Abstract Crotonyl‐CoA (cr‐CoA) is a metabolite derived directly from the catabolism of lysine (Lys) and tryptophan (Trp) or from the β‐oxidation of fatty acids. In glioblastoma stem cells (GSCs), histone H4 crotonylation levels are significantly elevated, which appears to positively correlate with tumor growth. This increase in crotonyl‐CoA production is attributed to the overexpression of specific Lys transporters on the cell membrane, leading to higher free lysine levels. Additionally, the overexpression of glutaryl‐CoA dehydrogenase (GCDH), the enzyme responsible for crotonyl‐CoA production, further contributes to this increase. When GCDH is depleted or under a lysine‐restricted diet, genes involved in type I interferon (IFN) signaling are upregulated, resulting in tumor growth suppression. Type I interferons are a group of cytokines critical for antiviral responses and immunoregulation. This highlights how cancer cells exploit crotonylation to modulate the immune response. This work opens up new avenues for investigating how cancer cells rewire their metabolism to increase crotonylation and evade the immune system.