肿瘤细胞有着与正常细胞显著不同的能量代谢过程以支撑其恶性增生。研究表明M2型丙酮酸激酶（PKM2）特异性高表达于多种肿瘤细胞，并在肿瘤代谢中起关键作用。PKM2复杂的分子调控机制尚有很多空白，是肿瘤代谢领域的研究热点之一。我们前期研究发现PKM2蛋白多个赖氨酸位点被琥珀酰化修饰；其琥珀酰化水平受去琥珀酰化酶SIRT5负调控；琥珀酰化抑制PKM2丙酮酸激酶活性并促进其入核，促进肝癌细胞生长。本项目拟在此基础上，以肝癌为模型，利用蛋白质组学和细胞分子生物学等多种技术，进一步阐明PKM2琥珀酰化导致酶活下降的分子机制，琥珀酰化与其他翻译后修饰（如乙酰化、磷酸化等）交互应答的动态变化规律，PKM2入核后促进肿瘤细胞生长的机制。本研究能丰富人们对PKM2在肿瘤细胞能量代谢和生长过程中复杂调控机制的了解，并为以PKM2为分子靶点的抗肿瘤药物研发提供理论基础。

Altered energy metabolism is fundamental to the growth and survival of cancer cells. The pyruvate kinase isoform M2 (PKM2) is normally expressed in embryonic tissues but is specifically reexpressed in many cancers including HCC and thought to play a central role in tumor metabolism. The current understanding of PKM2 regulatory mechanisms underlying PKM2 expression and enzymatic activity is still in its infancy. Recently, PKM2 has attracted a great deal of attention. Our data revealed that a total of 6 sites on PKM2 were Lys succinylated. PKM2 is desuccinylated by SIRT5. Succinylation inhibits pyruvate kinase activity of PKM2, promotes the nuclear accumulation of PKM2 and links HCC cell proliferation. In this study, to appreciate the technical progress of proteomics and molecular cell biology, we will try to characterize the mechanism of succinylation negatively regulates PKM2 activity, the cross-talk of succinylation with acetylation and phosphorylation, the relationship of PKM2 succinylation and cell energy homeostasis，the reason to promote cancer cell proliferation after nuclear accumulation of PKM2 rising. We hope that our studies will unearth the important mechanisms underlying PKM2 expression during tumor cell energy homeostasis and tumor development.