PI3Kβ functions as a protein kinase to promote cellular protein O-GlcNAcylation and acetyl-CoA production for tumor growth

Abstract

Phosphatidylinositol 3-kinase (PI3K) phosphorylates PI(4,5)P₂ to produce PI(3,4,5)P₃, thereby activating AKT and other effector proteins. However, whether PI3K has non-PI(3,4,5)P₃-related functions critical for tumor development remains unclear. Here, we demonstrate that high glucose induces PI3Kβ binding to O-linked β-D-N-acetylglucosamine (O-GlcNAc) transferase (OGT) in glioblastoma cells, dependent on hexokinase 1 (HK1)-mediated OGT Y889 phosphorylation and subsequent p85α recruitment. Importantly, PI3Kβ functions as a protein kinase, phosphorylating OGT at T985 and enhancing OGT activity and total cellular protein O-GlcNAcylation. Activated OGT O-GlcNAcylates ATP-citrate synthase (ACLY) at T639 and S667, leading to ACLY activation-dependent acetyl-coenzyme A (CoA) production to increase fatty acid levels and histone H3 acetylation for gene transcription. Intervention in PI3Kβ-mediated OGT phosphorylation and ACLY O-GlcNAcylation inhibits glioblastoma cell proliferation and tumor growth in xenografts. These findings underscore the critical role of PI3Kβ in governing protein O-GlcNAcylation, fatty acid metabolism, and chromatin modification through its protein kinase activity and provide instrumental insight into the roles of PI3K in tumor progression.