The oncoprotein HBXIP promotes glucose metabolism reprogramming via downregulating SCO2 and PDHA1 in breast cancer.

Fabao Liu,Yunxia Liu,Yinghui Li,Xiaodong Zhang,Xiaona You,Weiying Zhang,Yue Wang,Zhen Wang,Lihong Ye

doi:10.18632/oncotarget.4508

Abstract

The glucose metabolism reprogramming is a hallmark of cancer. The oncoprotein hepatitis B X-interacting protein (HBXIP) functions in the development of breast cancer. In this study, we supposed that HBXIP might be involved in the glucose metabolism reprogramming in breast cancer. We showed that HBXIP led to increases in generation of intracellular glucose and lactate, as well as decreases in generation of reactive oxygen species. Expression of synthesis of cytochrome c oxidase 2 (SCO2) and pyruvate dehydrogenase alpha 1 (PDHA1), two factors of metabolic switch from oxidative phosphorylation to aerobic glycolysis, was suppressed by HBXIP. In addition, miR-183/182 and miR-96 directly inhibited the expression of SCO2 and PDHA1 through targeting their mRNA coding sequences (CDSs), respectively. Interestingly, HBXIP elevated the miR-183/96/182 cluster expression through hypoxia-inducible factor 1α (HIF1α). The stability of HIF1α was enhanced by HBXIP through disassociating interaction of von Hippel-Lindau protein (pVHL) with HIF1α. Moreover, miR-183 increased the levels of HIF1α protein through directly targeting CDS of VHL mRNA, forming a feedback loop of HIF1α/miR-183/pVHL/HIF1α. In function, HBXIP-elevated miR-183/96/182 cluster enhanced the glucose metabolism reprogramming in vitro. HBXIP-triggered glucose metabolism reprogramming promoted the growth of breast cancer in vivo. Thus, we conclude that the oncoprotein HBXIP enhances glucose metabolism reprogramming through suppressing SCO2 and PDHA1 in breast cancer.

Highlights

Most cancer cells rely on aerobic glycolysis to generate the energy needed by cellular processes, which is termed the “Warburg effect” [1,2,3]
We uncovered that hepatitis B X-interacting protein (HBXIP) significantly increased generation of lactate and intracellular glucose and reduced intracellular reactive oxygen species (ROS) in MCF-7 and T47D cells (Figure 1A–1C), suggesting that HBXIP might be associated with the glucose metabolism reprogramming
The treatment with si-p53/si-HBXIP resulted in inhibition of the event in both MCF-7 and T47D cells (Supplementary Figure 1A), the interference efficiency of si-p53 and si-HBXIP was confirmed by Western blot analysis, suggesting that HBXIP affects the glucose metabolism reprogramming in a p53-independent manner

Summary

Introduction

Most cancer cells rely on aerobic glycolysis to generate the energy needed by cellular processes, which is termed the “Warburg effect” [1,2,3]. Much of the metabolic variation among individuals is genetically defined, the mutations in oncogenes (e.g., c-Myc and HIF1) and tumor suppressor genes (e.g., p53 and PTEN), which tend to enhance aerobic glycolysis and energy production, may represent a well-recognized mechanism [2, 4]. Human synthesis of cytochrome c oxidase 2 (SCO2), a novel p53-inducible protein, is a cytochrome c oxidase (COX) assembly protein that participates in the energy-generating metabolic pathways mediated by p53 through modulating the balance between the utilization of respiratory and glycolytic pathways [2, 5,6,7,8,9]. PDHA1 knockdown results in enhanced glucose uptake, rate of glycolysis and lactate production in H460-con cells [15]

Methods

Results

Conclusion