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

Xuxiao He; Deyu Chen; Guijun Liu; Qingang Wu; Hong Zhao; Dong Guo; Xiaoming Jiang; Min Li; Ying Meng; Yucheng Yin; Xianglai Ye; Shudi Luo; Yan Xia; Tony Hunter; Zhimin Lu

doi:10.1016/j.molcel.2025.02.024

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

Mol Cell. 2025 Apr 3;85(7):1411-1425.e8. doi: 10.1016/j.molcel.2025.02.024. Epub 2025 Mar 24.

Authors

Xuxiao He¹, Deyu Chen¹, Guijun Liu¹, Qingang Wu¹, Hong Zhao¹, Dong Guo¹, Xiaoming Jiang¹, Min Li¹, Ying Meng¹, Yucheng Yin¹, Xianglai Ye¹, Shudi Luo¹, Yan Xia², Tony Hunter³, Zhimin Lu⁴

Affiliations

¹ Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China; Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou 310029, Zhejiang, China.
² Department of Neuro-Oncology and Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
³ Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA.
⁴ Zhejiang Key Laboratory of Pancreatic Disease, The First Affiliated Hospital, Zhejiang Key Laboratory of Frontier Medical Research on Cancer Metabolism, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou 310029, Zhejiang, China; Institute of Fundamental and Transdisciplinary Research, Cancer Center, Zhejiang University, Hangzhou 310029, Zhejiang, China. Electronic address: zhiminlu@zju.edu.cn.

PMID: 40132583
DOI: 10.1016/j.molcel.2025.02.024

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.

Keywords: ACLY; HK1; OGT; PI3K; acetyl-CoA; fatty acid production; histone; tumor.

MeSH terms

Acetyl Coenzyme A* / biosynthesis
Acetyl Coenzyme A* / metabolism
Acetylation
Animals
Cell Line, Tumor
Cell Proliferation
Glioblastoma* / enzymology
Glioblastoma* / genetics
Glioblastoma* / metabolism
Glioblastoma* / pathology
Glucose / metabolism
Histones / metabolism
Humans
Mice
Mice, Nude
N-Acetylglucosaminyltransferases* / genetics
N-Acetylglucosaminyltransferases* / metabolism
Phosphorylation

Substances

N-Acetylglucosaminyltransferases
Acetyl Coenzyme A
OGT protein, human
Glucose
Histones