PKM2 Phosphorylates Histone H3 and Promotes Gene Transcription and Tumorigenesis

被引：710

作者：

Yang, Weiwei ^{[1
,2
]}

Xia, Yan ^{[1
,2
]}

Hawke, David ^{[3
]}

Li, Xinjian ^{[1
,2
]}

Liang, Ji ^{[1
,2
]}

Xing, Dongming ^{[6
]}

Aldape, Kenneth ^{[4
]}

Hunter, Tony ^{[7
]}

Yung, W. K. Alfred ^{[1
,2
]}

Lu, Zhimin ^{[1
,2
,5
,8
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Brain Tumor Ctr, Houston, TX 77030 USA

[2] Univ Texas MD Anderson Canc Ctr, Dept Neurooncol, Houston, TX 77030 USA

[3] Univ Texas MD Anderson Canc Ctr, Dept Mol Pathol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[5] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[6] Tsinghua Univ, Sch Life Sci, Lab Pharmaceut Sci, Beijing 100084, Peoples R China

[7] Salk Inst Biol Studies, Mol & Cell Biol Lab, La Jolla, CA 92037 USA

[8] Univ Texas Grad Sch Biomed Sci Houston, Houston, TX 77030 USA

来源：

CELL | 2012年 / 150卷 / 04期

关键词：

PYRUVATE-KINASE M2; BETA-CATENIN TRANSACTIVATION; NUCLEAR TRANSLOCATION; DOWN-REGULATION; METABOLISM; ACTIVATION; EXPRESSION; MITOSIS; GROWTH; EGFR;

D O I：

10.1016/j.cell.2012.07.018

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：685 / 696

页数：12

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