PKM2 磷酸化组蛋白 H3，促进基因转录和肿瘤发生。
PKM2 phosphorylates histone H3 and promotes gene transcription and tumorigenesis.
机构信息
Brain Tumor Center and Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
出版信息
Cell. 2012 Aug 17;150(4):685-96. doi: 10.1016/j.cell.2012.07.018.
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.
肿瘤特异性丙酮酸激酶 M2（PKM2）对于瓦博格效应至关重要。除了在有氧糖酵解中的公认作用外，PKM2 还直接调节基因转录。然而，PKM2 这种非代谢功能的机制仍难以捉摸。我们在这里表明，PKM2 在表皮生长因子受体激活时直接与组蛋白 H3 结合，并使组蛋白 H3 在 T11 处发生磷酸化。这种磷酸化对于 HDAC3 从 CCND1 和 MYC 启动子区域的解离以及随后的组蛋白 H3 在 K9 处乙酰化是必需的。PKM2 依赖性组蛋白 H3 修饰对于 EGF 诱导的细胞周期蛋白 D1 和 c-Myc 的表达、肿瘤细胞增殖、细胞周期进程和脑肿瘤发生至关重要。此外，组蛋白 H3 T11 磷酸化水平与核 PKM2 表达水平、神经胶质瘤恶性程度和预后相关。这些发现强调了 PKM2 作为蛋白激酶在其非代谢功能的组蛋白修饰中的作用，这对于其基因表达和肿瘤发生的表观遗传调控至关重要。
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