Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2)
Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2)
复制标题
肝癌中自噬对糖酵解代谢的调节涉及 HK2（己糖激酶 2）的选择性自噬降解
DOI：
10.1080/15548627.2017.1381804
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发表时间：
2018-01-01
期刊：
影响因子：
13.3
通讯作者：
Zhu, Xiao-Feng
中科院分区：
文献类型：
--
作者：
Jiao, Lin;Zhang, Hai-Liang;Zhu, Xiao-Feng
受损的巨自噬/自噬和高水平的糖酵解在肝癌中普遍存在。然而，自噬和糖酵解代谢之间是否存在调节关系仍不清楚。在这项研究中，通过利用具有基础或受损自噬通量的癌细胞，我们证明了糖酵解活性与自噬水平呈负相关。己糖激酶2（HK 2）是催化葡萄糖转化为葡萄糖-6-磷酸的关键糖酵解酶，其自噬降解被发现参与自噬对糖酵解的调节。由E3连接酶TRAF 6催化的HK 2的Lys 63连接的泛素化对于随后由自噬受体蛋白SQSTM 1/p62识别HK 2进行选择性自噬降解过程是至关重要的。在人肝癌的组织芯片中，高HK 2表达和高SQSTM 1表达的组合显示出具有生物学和预后意义。此外，靶向HK 2的丙酮酸类似物3-BrPA在体外和体内显著降低自噬受损肿瘤的生长（p < 0.05）。通过证明自噬通过TRAF 6和SQSTM 1介导的遍在蛋白化系统对糖酵解的调节，我们的研究可能为开发糖酵解靶向治疗干预措施来治疗自噬损伤的肝癌开辟了一条途径。
Impaired macroautophagy/autophagy and high levels of glycolysis are prevalent in liver cancer. However, it remains unknown whether there is a regulatory relationship between autophagy and glycolytic metabolism. In this study, by utilizing cancer cells with basal or impaired autophagic flux, we demonstrated that glycolytic activity is negatively correlated with autophagy level. The autophagic degradation of HK2 (hexokinase 2), a crucial glycolytic enzyme catalyzing the conversion of glucose to glucose-6-phosphate, was found to be involved in the regulation of glycolysis by autophagy. The Lys63-linked ubiquitination of HK2 catalyzed by the E3 ligase TRAF6 was critical for the subsequent recognition of HK2 by the autophagy receptor protein SQSTM1/p62 for the process of selective autophagic degradation. In a tissue microarray of human liver cancer, the combination of high HK2 expression and high SQSTM1 expression was shown to have biological and prognostic significance. Furthermore, 3-BrPA, a pyruvate analog targeting HK2, significantly decreased the growth of autophagy-impaired tumors in vitro and in vivo (p < 0.05). By demonstrating the regulation of glycolysis by autophagy through the TRAF6- and SQSTM1-mediated ubiquitination system, our study may open an avenue for developing a glycolysis-targeting therapeutic intervention for treatment of autophagy-impaired liver cancer.