TY - JOUR
T1 - PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis
AU - Yang, Weiwei
AU - Xia, Yan
AU - Hawke, David
AU - Li, Xinjian
AU - Liang, Ji
AU - Xing, Dongming
AU - Aldape, Kenneth
AU - Hunter, Tony
AU - Alfred Yung, W. K.
AU - Lu, Zhimin
N1 - Funding Information:
This work was supported by National Cancer Institute grants 2R01CA109035 (Z.L.), 5 P50 CA127001-03, and CA16672 (Cancer Center Support Grant); a research grant (RP110252; Z.L.) from the Cancer Prevention and Research Institute of Texas (CPRIT); an American Cancer Society Research Scholar Award RSG-09-277-01-CSM (Z.L.); and a Sister Institution Network Fund from The University of Texas MD Anderson Cancer Center (Z.L.). T.H. is a Frank and Else Schilling American Cancer Society Professor, and work in his group was supported by National Cancer Institute grant 2R01CA082683.
PY - 2012/8/17
Y1 - 2012/8/17
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2012.07.018
DO - 10.1016/j.cell.2012.07.018
M3 - Article
C2 - 22901803
AN - SCOPUS:84865266173
SN - 0092-8674
VL - 150
SP - 685
EP - 696
JO - Cell
JF - Cell
IS - 4
ER -