Chen Tsan-Jan, Wu Chun-Hsien, Hung Mien-Chie, Wang Wen-Ching, Kung Hsing-Jien
Institute of Molecular and Cellular Biology, College of Life Sciences and Medicine, National Tsing Hua University, Hsinchu, Taiwan.
Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan.
J Biomed Sci. 2025 Aug 11;32(1):75. doi: 10.1186/s12929-025-01170-6.
Pyruvate kinase M2 (PKM2) is a key enzyme involved in glycolysis, yet its role in cancer extends far beyond metabolic flux. Unlike its isoform PKM1, PKM2 exhibits unique regulatory properties due to alternative splicing and dynamic structural plasticity, enabling it to translocate into the nucleus. Once nuclear, PKM2 functions as a signal receiver, gene programmer, and metabolic modulator by acting as a co-transcriptional activator and protein kinase. In this capacity, nPKM2 (nuclear PKM2) orchestrates the transcription of genes involved in glycolysis, lipogenesis, redox homeostasis, and cell cycle progression, thereby reinforcing the Warburg effect and promoting tumor growth, metastasis, and resistance to stress. In this regard, nPKM2 can be considered as the oncogenic component of PKM2. This review consolidates current knowledge on the structural basis of PKM2 assembly and the post-translational modifications that govern its oligomeric state and nuclear import. We also explore emerging therapeutic strategies aimed at targeting nPKM2, including small-molecule modulators that stabilize its cytosolic tetrameric form or disrupt its nuclear functions. Ultimately, the multifaceted roles of nuclear PKM2 underscore its significance as a critical oncoprotein and a promising target for precision cancer therapy.
丙酮酸激酶M2（PKM2）是参与糖酵解的关键酶，但其在癌症中的作用远远超出代谢通量。与它的同工型PKM1不同，PKM2由于可变剪接和动态结构可塑性而表现出独特的调节特性，使其能够转运到细胞核中。一旦进入细胞核，PKM2通过充当共转录激活因子和蛋白激酶，发挥信号接收器、基因编程器和代谢调节剂的作用。以这种能力，核PKM2（nPKM2）协调参与糖酵解、脂肪生成、氧化还原稳态和细胞周期进程的基因转录，从而增强瓦伯格效应并促进肿瘤生长、转移和对压力的抵抗。在这方面，nPKM2可被视为PKM2的致癌成分。本综述整合了关于PKM2组装的结构基础以及控制其寡聚状态和核输入的翻译后修饰的当前知识。我们还探讨了针对nPKM2的新兴治疗策略，包括稳定其胞质四聚体形式或破坏其核功能的小分子调节剂。最终，核PKM2的多方面作用凸显了其作为关键癌蛋白和精准癌症治疗的有前景靶点的重要性。
