Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition
Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition
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DOI：
10.1073/pnas.1407717111
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发表时间：
2014-10-28
影响因子：
11.1
通讯作者：
Ishii, Hideshi
中科院分区：
文献类型：
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作者：
Hamabe, Atsushi;Konno, Masamitsu;Ishii, Hideshi
丙酮酸激酶 M2 (PKM2) 是丙酮酸激酶基因的选择性剪接变体，在胚胎发育期间和癌细胞中优先表达。 PKM2 改变糖酵解的最终限速步骤，从而产生癌症特异性的 Warburg 效应（也称为有氧糖酵解）。尽管之前的报道表明 PKM2 在非代谢转录调控中发挥作用，但其在癌症生物学中的重要性仍然难以捉摸。在这里，我们报道刺激上皮间质转化（EMT）会导致结肠癌细胞中PKM2的核转位，这对于促进EMT至关重要。免疫沉淀和LC-电喷雾电离TOF MS分析表明，EMT刺激导致细胞核中的PKM2与TGF-β诱导因子同源盒2（TGIF2）（TGF-β信号转导的转录辅助因子阻遏物）直接相互作用。 PKM2 与 TGIF2 的结合将组蛋白脱乙酰酶 3 募集至 E-钙粘蛋白启动子序列，随后组蛋白 H3 脱乙酰并抑制 E-钙粘蛋白转录。这一先前未确认的 PKM2 在细胞核中分子相互作用的发现揭示了 PKM2 在癌细胞中表达的重要性。
Pyruvate kinase M2 (PKM2) is an alternatively spliced variant of the pyruvate kinase gene that is preferentially expressed during embryonic development and in cancer cells. PKM2 alters the final rate-limiting step of glycolysis, resulting in the cancer-specific Warburg effect (also referred to as aerobic glycolysis). Although previous reports suggest that PKM2 functions in nonmetabolic transcriptional regulation, its significance in cancer biology remains elusive. Here we report that stimulation of epithelial-mesenchymal transition (EMT) results in the nuclear translocation of PKM2 in colon cancer cells, which is pivotal in promoting EMT. Immunoprecipitation and LC-electrospray ionized TOF MS analyses revealed that EMT stimulation causes direct interaction of PKM2 in the nucleus with TGF-beta-induced factor homeobox 2 (TGIF2), a transcriptional cofactor repressor of TGF-beta signaling. The binding of PKM2 with TGIF2 recruits histone deacetylase 3 to the E-cadherin promoter sequence, with subsequent deacetylation of histone H3 and suppression of E-cadherin transcription. This previously unidentified finding of the molecular interaction of PKM2 in the nucleus sheds light on the significance of PKM2 expression in cancer cells.