Beijing Key Laboratory of DNA Damage Response and College of Life Sciences, Capital Normal University, Beijing, 100048, China.
Guangdong Key Laboratory for Genome Stability & Disease Prevention and Carson International Cancer Center and Marshall Laboratory of Biomedical Engineering, Shenzhen University School of Medicine, Shenzhen, Guangdong, 518060, China.
Oncogene. 2024 Jun;43(23):1769-1778. doi: 10.1038/s41388-024-03035-y. Epub 2024 Apr 17.
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.
丙酮酸激酶 M2（PKM2）是一种关键的代谢酶，可促进肿瘤生长的瓦博格效应。先前的研究表明，PKM2 可发生 O-链接 β-N-乙酰葡萄糖胺（O-GlcNAc）修饰，这是一种营养敏感的翻译后修饰。在这里，我们发现非典型卷曲螺旋激酶 1（ULK1）与 PKM2 相互作用，ULK1 是一种葡萄糖敏感的激酶，可磷酸化 PKM2 的丝氨酸 333 位（PKM2-Ser333）。丝氨酸 333 位磷酸化拮抗 PKM2 的 O-GlcNAc 化，促进其四聚体形成和酶活性，并减少其核定位。由于 PKM2 在核内调节 c-Myc 方面具有已知作用，我们还表明 PKM2-Ser333 磷酸化抑制 c-Myc 表达。通过下调葡萄糖消耗和乳酸生成，PKM2 pS333 减弱了瓦博格效应。通过小鼠异种移植实验，我们证明了磷酸化缺陷的 PKM2-S333A 突变体在体内促进肿瘤生长。总之，我们鉴定了一个在抑制乳腺癌中起作用的 ULK1-PKM2-c-Myc 轴，以及在调节瓦博格效应中起作用的 PKM2 葡萄糖敏感性磷酸化。
