PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis
By Weiwei Yang, Yan Xia, D. Hawke, Xinjian Li, Ji Liang, Dongming Xing, Kenneth D. Aldape, T. Hunter, W. Yung, Zhimin Lu. Cell, 2012
799 citations recorded by the source corpus.
SUMMARY Tumor-specific pyruvate kinase M2 (PKM2) is essential for the Warburg effect. Besides 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.
Subfields: Cancer Research, Cell Biology, Molecular Biology
View Paper: https://www.semanticscholar.org/paper/4d930f24c0df682a49b5f9da27db3b26aabed03a
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Citations in the corpus
- SIRT5-Mediated Lysine Desuccinylation Impacts Diverse Metabolic Pathways (2013, neutral): “Recent studies identified additional functional roles in the nucleus as a protein kinase regulating histone H3 and STAT3 phosphorylation (Gao et al., 2012; Yang et al., 2012).”
- The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. (2013, background): “Furthermore, the levels ofHP1a, theH3K9me3 reader, and Suz12 and Ezh2, two subunits of the PRC2 complex (Simon and Kingston 2009; Margueron and Reinberg 2011; Yang et al. 2012), were not altered significantly in these cells (Fig.”
- Tumor glycolysis as a target for cancer therapy: progress and prospects (2013, positive): “PK-M2 acts as a kinase and phosphorylates histone H3 to favor tumorigenesis [54], as a nuclear protein it transactivates β-catenin [55], and as a phosphotyrosine binding protein it interacts with other proteins as well [56].”