PDK1/ac-CoA介导组蛋白H4去乙酰化调控结肠癌EMT的机制研究

The increased aerobic glycolysis is one of distinguishing features of solid tumors, which confers a metastatic advantage to cancer cells. However, the roles of intermediate metabolites produced by aerobic glycolysis in epithelial-mesenchymal transition, the key process of metastasis, are still unknown. In our previous study, we discovered that pyruvate dehydrogenase kinase-1 (PDK1) is commonly high-expressed in cancer-positive lymph nodes of colon cancer patients. Human colon cancer cells exerts prominent mesenchymal phenotype by upregulating PDK1, which could be reversed by ac-CoA incorporation. We propose that PDK1 may regulate the EMT of colon cancer through an ac-CoA dependent pathway. In the present proposal, as an attempt to find out the potential PDK1-ac-CoA/H4-E-cadherin axis, we plan to elucidate the interaction between ac-CoA and H4, then to reveal the regulation of E-cadherin via ac-CoA-induced H4 acetylation. This study focuses on a novel mechanism that PDK1 acts on regulators of EMT via ac-CoA/H4-E-cadherin pathway, which may elucidate the molecular mechanism of EMT initiated by aerobic glycolysis and provide new target for tumor progression and epithelial-mesenchymal transition of colon cancer.

异常活跃的有氧糖酵解是促进肿瘤细胞侵袭转移的重要因素，但对处于异常能量代谢下的肿瘤细胞如何通过代谢物本身调控胞内信号，并启动上皮间质转化促进侵袭转移这一环节尚不清楚。我们前期研究发现结肠癌患者的淋巴结转移灶中糖酵解关键因子PDK1表达增加，过表达PDK1可促进结肠癌细胞EMT，通过掺入代谢物ac-CoA可抑制PDK1诱导的EMT作用，恢复其上皮表型。本项目拟在前期工作基础上，探讨PDK1经ac-CoA对EMT的影响，通过研究ac-CoA介导组蛋白H4的乙酰化修饰，明确H4的乙酰化修饰位点，继而研究H4的乙酰化修饰对E-cadherin的转录调控作用，以期证实PDK1通过ac-CoA/H4/E-cadherin途径调控EMT，阐明有氧糖酵解调控结肠癌EMT的分子机制。该研究不仅可从表观遗传学角度揭示肿瘤能量代谢与肿瘤侵袭转移的联系，而且可为阻断结肠癌细胞上皮间质转化和侵袭转移提供新的靶点。

肿瘤细胞通过中间代谢物启动上皮间质转化促进侵袭转移的机制尚不清楚。我们研究发现结肠癌患者的淋巴结转移灶中糖酵解关键因子 PDK1表达增加，过表达PDK1可促进结肠癌细胞EMT，通过掺入代谢物ac-CoA可抑制PDK1诱导的EMT作用，恢复其上皮表型。课题组研究发现PDK1可抑制中间代谢物ac-CoA的生成，进而增强肿瘤细胞的EMT，其机制是抑制了ac-CoA介导的组蛋白H4的乙酰化修饰，通过对E-cadherin的转录调控抑制E-cadherin表达。本研究证实了PDK1通过ac-CoA/H4/E-cadherin途径调控EMT，从表观遗传学角度揭示肿瘤能量代谢与肿瘤侵袭转移的联系。