B7-H3 promotes aerobic glycolysis and chemoresistance in colorectal cancer cells by regulating HK2

Tongguo Shi,Lei Cao,Weichang Chen,Xueguang Zhang,Binfeng Lu,Zhenxin Wang,Yunyun Xu,Huimin Lu,Yanchao Ma,Ruoqin Wang,Shenghua Zhan,Cuiping Liu,Fengqing Fu,Guangbo Zhang

doi:10.1038/s41419-019-1549-6

Abstract

Accumulating evidence suggests that aerobic glycolysis is important for colorectal cancer (CRC) development. However, the underlying mechanisms have yet to be elucidated. B7-H3, an immunoregulatory protein, is broadly overexpressed by multiple tumor types and plays a vital role in tumor progression. In this study, we found that overexpression of B7-H3 effectively increased the rate of glucose consumption and lactate production, whereas knockdown of B7-H3 had the opposite effect. Furthermore, we showed that B7-H3 increased glucose consumption and lactate production by promoting hexokinase 2 (HK2) expression in CRC cells, and we also found that HK2 was a key mediator of B7-H3-induced CRC chemoresistance. Depletion of HK2 expression or treating cells with HK2 inhibitors could reverse the B7-H3-induced increase in aerobic glycolysis and B7-H3-endowed chemoresistance of cancer cells. Moreover, we verified a positive correlation between the expression of B7-H3 and HK2 in tumor tissues of CRC patients. Collectively, our findings suggest that B7-H3 may be a novel regulator of glucose metabolism and chemoresistance via controlling HK2 expression in CRC cells, a result that could help develop B7-H3 as a promising therapeutic target for CRC treatment.

Highlights

Colorectal cancer (CRC) is the third most prevalent cancer type in the world[1]
B7-H3 controls expression of hexokinase 2 (HK2) via STAT3 To investigate how B7-H3 regulates aerobic glycolysis in CRC, we analyzed the expression of a spectrum of key glycolysis-related genes, including Glucose transporter 1 (GLUT1), Glucose transporter 4 (GLUT4), Lactate dehydrogenase A (LDHA), Lactate dehydrogenase B (LDHB), HK2, pyruvate kinase M 2 (PKM2), hypoxiainducible factor 1α (HIF-1α) and pyruvate dehydrogenase kinase 1 (PDK1) in B7-H3overexpressing HCT116, and RKO cells with real-time quantitative PCR (RT-qPCR) (Fig. 2a, b)
We found that the expression level of HK2, a known mediator of aerobic glycolysis, was the most increased in both HCT116 and RKO cells with overexpression of B7-H3 (Fig. 2a, b)

Summary

Introduction

Colorectal cancer (CRC) is the third most prevalent cancer type in the world[1]. B7-H3, known as CD276, is an important immune checkpoint member of the B7-CD28 family[3]. As a type I transmembrane protein, two B7-H3 isoforms (4IgB7-H3 and 2Ig-B7-H3) have been identified; 4Ig-B7-H3 is the main isoform in humans and 2Ig-B7-H3 is the only isoform in mice[4]. Because of the lack of an identified receptor, the immunologic function of B7-H3 remains controversial, with conflicting costimulatory and coinhibitory functions[5]. B7-H3 has been reported to be a pivotal non-immunologically multifunctional protein involved in the regulation of many key cellular events. Accumulated evidence indicates that aberrant expression of B7-H3 is a common characteristic of CRC and is consistently correlated with poor patient prognosis, suggesting its emerging importance in CRC

Methods

Results

Conclusion