Regulation of glycolytic metabolism by autophagy in liver cancer involves selective autophagic degradation of HK2 (hexokinase 2)

ABSTRACT

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.

KEYWORDS:

• autophagy
• glycolysis
• hexokinase 2
• liver cancer
• SQSTM1/p62
• TRAF6
• ubiquitination

Acknowledgments

We thank Dr. Minshan Chen and Dr. Keli Yang (Department of Hepatobiliary Surgery, Sun Yat-sen University Cancer Center) for providing the microarrays of liver cancer tissues, Dr. Peng Huang (MD Anderson Cancer Center) for providing helpful and intensive discussions, Dr. Xinke Zhang (Department of Pathology, Sun Yat-sen University Cancer Center) for support with immunohistochemical scoring and Dr. Xinxing Lei for the excellent graphical abstract.

Disclosure of potential conflicts of interest

No potential conflicts of interest are disclosed.

Grant support

This work was supported by the Natural Science Foundation of China under grants 81572732, 81630079, 81572493, 81572605, 81702288 and 81772624; the Science and Technology project of Guangdong Province under grants 2014B050504004, 2015B050501005 and 2017A020215032; the Natural Science Foundation of Guangdong in China under grant 2014A030313010, 2014A030313017, the Major Science and Technology Project of Guangzhou under grants 201504010038 and 201707010086; the Fundamental Research Funds for the Central Universities 17ykjc25.

Additional information

Funding

This work was supported by the Natural Science Foundation of China under grants 81572732, 81630079, 81572493, 81572605, 81702288 and 81772624; the Science and Technology project of Guangdong Province under grants 2014B050504004, 2015B050501005 and 2017A020215032; the Natural Science Foundation of Guangdong in China under grant 2014A030313010, 2014A030313017, the Major Science and Technology Project of Guangzhou under grants 201504010038 and 201707010086; the Fundamental Research Funds for the Central Universities 17ykjc25.