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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.

Titel:	ULK1-dependent phosphorylation of PKM2 antagonizes O-GlcNAcylation and regulates the Warburg effect in breast cancer.
Autor/in / Beteiligte Person:	Zhou, Z ; Zheng, X ; Zhao, J ; Yuan, A ; Lv, Z ; Shao, G ; Peng, B ; Dong, MQ ; Xu, Q ; Xu, X ; Li, J
Link:	Zum Volltext
Zeitschrift:	Oncogene, Jg. 43 (2024-06-01), Heft 23, S. 1769
Veröffentlichung:	<2002->: Basingstoke : Nature Publishing Group ; <i>Original Publication</i>: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-, 2024
Medientyp:	academicJournal
ISSN:	1476-5594 (electronic)
DOI:	10.1038/s41388-024-03035-y
Schlagwort:	Humans Phosphorylation Animals Female Mice Cell Line, Tumor Proto-Oncogene Proteins c-myc metabolism Proto-Oncogene Proteins c-myc genetics Acetylglucosamine metabolism Autophagy-Related Protein-1 Homolog metabolism Autophagy-Related Protein-1 Homolog genetics Breast Neoplasms metabolism Breast Neoplasms pathology Breast Neoplasms genetics Thyroid Hormones metabolism Thyroid Hormones genetics Thyroid Hormone-Binding Proteins Membrane Proteins metabolism Membrane Proteins genetics Carrier Proteins metabolism Carrier Proteins genetics Intracellular Signaling Peptides and Proteins metabolism Intracellular Signaling Peptides and Proteins genetics Warburg Effect, Oncologic
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article Language: English [Oncogene] 2024 Jun; Vol. 43 (23), pp. 1769-1778. <i>Date of Electronic Publication: </i>2024 Apr 17. MeSH Terms: Autophagy-Related Protein-1 Homolog* / metabolism ; Autophagy-Related Protein-1 Homolog* / genetics ; Breast Neoplasms* / metabolism ; Breast Neoplasms* / pathology ; Breast Neoplasms* / genetics ; Thyroid Hormones* / metabolism ; Thyroid Hormones* / genetics ; Thyroid Hormone-Binding Proteins* ; Membrane Proteins* / metabolism ; Membrane Proteins* / genetics ; Carrier Proteins* / metabolism ; Carrier Proteins* / genetics ; Intracellular Signaling Peptides and Proteins* / metabolism ; Intracellular Signaling Peptides and Proteins* / genetics ; Warburg Effect, Oncologic* ; Humans ; Phosphorylation ; Animals ; Female ; Mice ; Cell Line, Tumor ; Proto-Oncogene Proteins c-myc / metabolism ; Proto-Oncogene Proteins c-myc / genetics ; Acetylglucosamine / metabolism References: Cairns RA, Harris IS, Mak TW. Regulation of cancer cell metabolism. Nat Rev Cancer. 2011;11:85–95. (PMID: 10.1038/nrc298121258394) ; Vander Heiden MG, Cantley LC, Thompson CB. 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(PMID: 10.1093/nar/gky86930252093) Grant Information: 32271285,31872720 National Natural Science Foundation of China (National Science Foundation of China); 32090031 National Natural Science Foundation of China (National Science Foundation of China) Substance Nomenclature: EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog) ; EC 2.7.11.1 (ULK1 protein, human) ; 0 (Thyroid Hormones) ; 0 (Thyroid Hormone-Binding Proteins) ; 0 (Membrane Proteins) ; 0 (Carrier Proteins) ; 0 (Intracellular Signaling Peptides and Proteins) ; 0 (Proto-Oncogene Proteins c-myc) ; V956696549 (Acetylglucosamine) ; 0 (MYC protein, human) Entry Date(s): Date Created: 20240417 Date Completed: 20240607 Latest Revision: 20240617 Update Code: 20240617

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