ULK1-dependent phosphorylation of PKM2 antagonizes O-GlcNAcylation and regulates the Warburg effect in breast cancer

• Published in: Oncogene Vol. 43; no. 23; pp. 1769 - 1778
• Main Authors: Zhou, Zibin, Zheng, Xiyuan, Zhao, Jianxin, Yuan, Aiyun, Lv, Zhuan, Shao, Guangcan, Peng, Bin, Dong, Meng-Qiu, Xu, Quan, Xu, Xingzhi, Li, Jing
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.06.2024; Nature Publishing Group
• Subjects: 101/58; 13/95; 45/70; 631/45/221; 631/80/458/1733; 96/1; 96/109; 96/63; Acetylglucosamine - metabolism; Animals; Antibodies; Apoptosis; Autophagy; Autophagy-Related Protein-1 Homolog - genetics; Autophagy-Related Protein-1 Homolog - metabolism; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; c-Myc protein; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Biology; Cell Line, Tumor; Enzymatic activity; Enzymes; Female; Glucose; Human Genetics; Humans; Internal Medicine; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - metabolism; Kinases; Localization; Mass spectrometry; Medicine; Medicine & Public Health; Membrane Proteins - genetics; Membrane Proteins - metabolism; Metabolism; Mice; Myc protein; N-Acetylglucosamine; O-GlcNAcylation; Oncology; Phosphorylation; Plasmids; Post-translation; Proto-Oncogene Proteins c-myc - genetics; Proto-Oncogene Proteins c-myc - metabolism; Pyruvate kinase; Pyruvic acid; Scientific imaging; Thyroid Hormone-Binding Proteins; Thyroid Hormones - genetics; Thyroid Hormones - metabolism; Tumors; Warburg Effect, Oncologic
• ISSN: 0950-9232; 1476-5594; 1476-5594
• DOI: 10.1038/s41388-024-03035-y

Pyruvate kinase M2 (PKM2) is a central metabolic enzyme driving the Warburg effect in tumor growth. Previous investigations have demonstrated that PKM2 is subject to O-linked β-N-acetylglucosamine (O-GlcNAc) modification, which is a nutrient-sensitive post-translational modification. Here we found that unc-51 like autophagy activating kinase 1 (ULK1), a glucose-sensitive kinase, interacts with PKM2 and phosphorylates PKM2 at Ser333. Ser333 phosphorylation antagonizes PKM2 O-GlcNAcylation, promotes its tetramer formation and enzymatic activity, and decreases its nuclear localization. As PKM2 is known to have a nuclear role in regulating c-Myc, we also show that PKM2-S333 phosphorylation inhibits c-Myc expression. By downregulating glucose consumption and lactate production, PKM2 pS333 attenuates the Warburg effect. Through mouse xenograft assays, we demonstrate that the phospho-deficient PKM2-S333A mutant promotes tumor growth in vivo. In conclusion, we identified a ULK1-PKM2-c-Myc axis in inhibiting breast cancer, and a glucose-sensitive phosphorylation of PKM2 in modulating the Warburg effect.