Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulator
Abstract 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...
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| Format: | Article |
| Language: | English |
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BMC
2025-08-01
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| Series: | Journal of Biomedical Science |
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| Online Access: | https://doi.org/10.1186/s12929-025-01170-6 |
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| author | Tsan-Jan Chen Chun-Hsien Wu Mien-Chie Hung Wen-Ching Wang Hsing-Jien Kung |
| author_facet | Tsan-Jan Chen Chun-Hsien Wu Mien-Chie Hung Wen-Ching Wang Hsing-Jien Kung |
| author_sort | Tsan-Jan Chen |
| collection | DOAJ |
| description | Abstract 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. |
| format | Article |
| id | doaj-art-af6715cf1430446cafad9722cdb2103a |
| institution | Kabale University |
| issn | 1423-0127 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Biomedical Science |
| spelling | doaj-art-af6715cf1430446cafad9722cdb2103a2025-08-20T04:03:02ZengBMCJournal of Biomedical Science1423-01272025-08-0132112210.1186/s12929-025-01170-6Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulatorTsan-Jan Chen0Chun-Hsien Wu1Mien-Chie Hung2Wen-Ching Wang3Hsing-Jien Kung4Institute of Molecular and Cellular Biology, College of Life Sciences and Medicine, National Tsing Hua UniversityGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityGraduate Institute of Biomedical Sciences and Center for Molecular Medicine, China Medical UniversityInstitute of Molecular and Cellular Biology, College of Life Sciences and Medicine, National Tsing Hua UniversityGraduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical UniversityAbstract 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.https://doi.org/10.1186/s12929-025-01170-6Nuclear PKM2Nuclear translocationPost-translational modificationOncogenic signalingCancer metabolismSignal receiver |
| spellingShingle | Tsan-Jan Chen Chun-Hsien Wu Mien-Chie Hung Wen-Ching Wang Hsing-Jien Kung Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulator Journal of Biomedical Science Nuclear PKM2 Nuclear translocation Post-translational modification Oncogenic signaling Cancer metabolism Signal receiver |
| title | Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulator |
| title_full | Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulator |
| title_fullStr | Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulator |
| title_full_unstemmed | Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulator |
| title_short | Nuclear PKM2: a signal receiver, a gene programmer, and a metabolic modulator |
| title_sort | nuclear pkm2 a signal receiver a gene programmer and a metabolic modulator |
| topic | Nuclear PKM2 Nuclear translocation Post-translational modification Oncogenic signaling Cancer metabolism Signal receiver |
| url | https://doi.org/10.1186/s12929-025-01170-6 |
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