PRAS40 promotes colorectal cancer stemness by enhancing glycolysis through triggering PGK1 acetylation.

Cancer stem cells (CSCs) play a pivotal role in driving colorectal cancer (CRC) progression and therapeutic resistance. However, the molecular mechanisms regulating CRC-CSC properties are not fully understood. Proline-rich Akt substrate 40 (PRAS40) is involved in various tumorigenic processes, yet little is known about its contribution to cancer stemness. In this study, we demonstrated that PRAS40 was overexpressed in CRC tissues and its elevated expression positively correlated with poor patient survival. Genetic ablation of PRAS40 suppressed tumorigenesis in CRC mouse models. Notably, PRAS40 enhanced the stemness of CRC cells, as evidenced by increased sphere formation, upregulation of stem cell markers, enrichment of the CD133CD44 cell population, and enhanced tumor initiation capacity in vivo. Mechanistically, PRAS40 induced a glycolytic phenotype by interacting with and activating the glycolytic enzyme phosphoglycerate kinase 1 (PGK1). Furthermore, PRAS40 enhanced the interaction between PGK1 and the acetyltransferase p300/CBP-associated factor (PCAF), thereby promoting PGK1 acetylation, which contributes to glycolysis activation and the maintenance of CRC stemness. Pharmacological inhibition of acetylation attenuated PRAS40-mediated CRC stemness and colorectal carcinogenesis. Collectively, our findings uncover a novel PRAS40/PGK1 regulatory axis that promotes CRC stemness and tumorigenesis through enhanced glycolysis, suggesting potential therapeutic strategies targeting this axis for CRC treatment.