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Crucial Role of RLIP76 in Promoting Glycolysis and Tumorigenesis by Stabilization of HIF-1α in Glioma Cells Under Hypoxia

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Abstract

Hypoxia is intimately associated with enhanced glycolysis in gliomas, and hypoxia-inducible factor 1α (HIF-1α) plays a critical role in this process. RLIP76 (Ral-interacting protein 76) functions as a multifunctional mediator and is aberrantly expressed in various malignant tumors, including glioma. However, the underlying mechanism of RLIP76 and HIF-1α in glioma glycolysis remains largely unclear. In the present study, we demonstrated that RLIP76 is a hypoxia-inducible molecule that contributes to facilitating glycolysis in glioma cells under hypoxic conditions. In addition, hypoxia-induced RLIP76 is a novel target of HIF-1α and enhances the two important HIF-1α-target glycolytic proteins glucose transporter type 1 (GLUT1) and lactate dehydrogenase A (LDHA) in hypoxia. Mechanistically, RLIP76 can directly bind to HIF-1α in the nucleus and regulate the stability of HIF-1α by alleviating HIF-1α ubiquitination and therefore activates GLUT1 and LDHA to accelerate glycolysis in hypoxia. Furthermore, the enhanced glycolysis is necessary for the role of RLIP76 to promote glioma development in vivo, confirming the ability of RLIP76 to regulate tumor cell glycolysis. Collectively, our results demonstrate a previously unappreciated function of RLIP76 in hypoxia-mediated glycolytic metabolism and implicate that RLIP76 might be a valuable therapeutic target for gliomas.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Abbreviations

AKT:

Protein kinase B

ATP:

Adenosine triphosphate

ECAR:

Extracellular acidification rate

FDR:

False discovery rate

GBM:

Glioblastoma

GLUT1:

Glucose transporter type 1

GO:

Gene ontology

GTP:

Guanosine triphosphate

HIF-1α:

Hypoxia-inducible factor 1α

HRE:

Hypoxia response element

Hsf-1:

Heat shock factor-1

KEGG:

Kyoto Encyclopedia of Genes and Genomes

LDHA:

Lactate dehydrogenase A

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Funding

This study was funded by the National Science Foundation of China (grant no. 81802489) and the Shanghai Natural Science Foundation (grant no. 19ZR1448900).

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  1. Qi Wang and Chi Zhang contributed equally to this work.

Authors and Affiliations

  1. Department of Neurosurgery, Shanghai Tongji Hospital, Tongji University School of Medicine, 389 Xincun Road, Shanghai, China

    Qi Wang, Chi Zhang, Junle Zhu, Lei Zhang, Huairui Chen, Jun Qian & Chun Luo

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  1. Qi Wang
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Contributions

C. Z. and Q. W. were responsible for designing the study and writing the manuscript. L. Z. and H. R. C. were responsible for the data analysis. J. Q. was responsible for editing the manuscript. J. L. Z. and C. L. were responsible for re-editing the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Chun Luo.

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All the patients were informed of sample collection and usage. The tissue samples were collected and used in accordance with approval by the Specialty Committee on Ethics of Biomedicine Research, Shanghai Tongji University (PJ2015-011–08). Use of animal was approved by the Shanghai Tongji Hospital Animal Ethics Committee.

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Wang, Q., Zhang, C., Zhu, J. et al. Crucial Role of RLIP76 in Promoting Glycolysis and Tumorigenesis by Stabilization of HIF-1α in Glioma Cells Under Hypoxia. Mol Neurobiol 59, 6724–6739 (2022). https://doi.org/10.1007/s12035-022-02999-w

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