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PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis
Open accessAbstract
Tumor-specific pyruvate kinase M2 (PKM2) is essential for the Warburg effect. In addition to its well-established role in aerobic glycolysis, PKM2 directly regulates gene transcription. However, the mechanism underlying this nonmetabolic function of PKM2 remains elusive. We show here that PKM2 directly binds to histone H3 and phosphorylates histone H3 at T11 upon EGF receptor activation. This phosphorylation is required for the dissociation of HDAC3 from the CCND1 and MYC promoter regions and subsequent acetylation of histone H3 at K9. PKM2-dependent histone H3 modifications are instrumental in EGF-induced expression of cyclin D1 and c-Myc, tumor cell proliferation, cell-cycle progression, and brain tumorigenesis. In addition, levels of histone H3 T11 phosphorylation correlate with nuclear PKM2 expression levels, glioma malignancy grades, and prognosis. These findings highlight the role of PKM2 as a protein kinase in its nonmetabolic functions of histone modification, which is essential for its epigenetic regulation of gene expression and tumorigenesis.
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“PKM2 may also exert some of its effects on cell proliferation through nonmetabolic functions, including transcriptional and epigenetic regulation (61, 62).”
From Fueling Immunity: Insights into Metabolism and Lymphocyte Function (2013) · cites this paper as [62]
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Metadata
- Authors
- Yang, W., Xia, Y., Hawke, D., Li, X., Liang, J., Xing, D., Aldape, K., Hunter, T., Alfred Yung, W. K., & Lu, Z.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Tsinghua University (CN)
- Salk Institute for Biological Studies (US)
- Corresponding author
- Lu, Zhimin
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2012-08
- Volume
- 150
- Issue
- 4
- Pages
- 685-696
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3431020
- OpenAlex
- W2134847995
- Cited by
- 846
- References
- 48
- Citations by year
- 2026: 46 · 2025: 66 · 2024: 63 · 2023: 85 · 2022: 45 · 2021: 75 · 2020: 62 · 2019: 68 · 2018: 58 · 2017: 54 · 2016: 64 · 2015: 51 · 2014: 52 · 2013: 43 · 2012: 9
- FWCI
- 16.46
- Type
- journal article
- Language
- en
- Update notices
- erratum (2014-08-28)
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (CA-16672, R01CA109035, R01CA082683, P30CA016672, P50CA127001)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Keywords
- PKM2, HDAC3, EGF receptor, cyclin D1, c-Myc, gene transcription, epigenetic regulation, Warburg effect, aerobic glycolysis, brain tumorigenesis, glioma, tumor cell proliferation, cell cycle progression
- MeSH terms
- Thyroid Hormone-Binding Proteins, Animals, Astrocytoma, Carrier Proteins, Cell Line, Cell Transformation, Neoplastic, Epidermal Growth Factor, Female, Glioblastoma, Histones, Humans, Membrane Proteins, Mice, Nude, Neoplasm Transplantation, Thyroid Hormones, Transcription, Genetic, Transplantation, Heterologous, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins c-myc, Cyclin D1, Epigenesis, Genetic, Cell Line, Tumor, Mice
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