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EGFR activates GDH1 transcription to promote glutamine metabolism through MEK/ERK/ELK1 pathway in glioblastoma

Oncogene volume 39, pages 2975–2986 (2020)Cite this article

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A Correction to this article was published on 12 July 2022

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Abstract

Cancer metabolism research has recently been revived and its focus expanded from glucose and the Warburg’s effects on other nutrients, such as glutamine. The underlying mechanism of oncogenic alterations of glutaminolysis remains unclear. Genetic alterations of EGFR are observed in ~50% of glioblastoma (GBM) patients, and have been found to play important roles in the metabolic abnormalities of GBM. In this study, we found that glutamine metabolism was upregulated after EGFR activation in a GDH1 (glutamate dehydrogenase 1)-dependent manner. Knockdown of GDH1 significantly reduced the cell proliferation, colony formation and tumorigenesis abilities of glioblastoma cells. Furthermore, we showed that GDH1-mediated glutaminolysis was involved in EGF-promoted cell proliferation. EGFR triggered the phosphorylation of ELK1 at Ser 383 through activating MEK/ERK signaling. Phosphorylated ELK1 enriched in the promoter of GDH1 to activate the transcription of GDH1, which then promoted glutamine metabolism. In addition, EGFR activation did not accelerate glutaminolysis in ELK1 knockdown or ELK1 Ser383-mutated cells. Collectively, our findings indicate that EGFR phosphorylates ELK1 to activate GDH1 transcription and glutaminolysis through MEK/ERK pathway, providing new insight into oncogenic alterations of glutamine metabolism.

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Fig. 1: EGFR activation promotes glutamine metabolism in a GDH1-dependent manner.
Fig. 2: GDH1 is required for cell proliferation and tumor growth in GBM.
Fig. 3: GDH1-mediated glutaminolysis is involved in regulation of EGF-promoted proliferation in GBM cells.
Fig. 4: ELK1 promote the transcription of GDH1.
Fig. 5: EGFR promotes GDH1 transcription by activating MEK/ERK/ELK1 signaling pathway.
Fig. 6: EGFR promotes glutaminolysis through ELK1-GDH1 axis.

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Acknowledgements

This research was supported by the National Natural Science Foundation of China (Nos. 81672502 and 81872071), the grant to the Key Laboratory of Higher Education Institutes of Shandong Province, the National Natural Science Foundation Cultivation Project of Jining Medical University (600788002) and Faculty Startup Fund for RY from Jining Medical University (600788001).

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Authors and Affiliations

  1. Key Laboratory of Precision Oncology of Shandong Higher Education, Institute of Precision Medicine, Jining Medical University, Jining, China

    Rui Yang, Xiaoran Liu, Yanping Li, Yonghua Bao & Wancai Yang

  2. State Key Laboratory of Silkworm Genome Biology, Southwest University, Chongqing, China

    Rui Yang, Yanan Wu, Guanghui Zhang & Hongjuan Cui

  3. Department of Pharmacy, The Second People’s Hospital of Liaocheng, Liaocheng, China

    Xiuxiu Li

  4. Cancer Center, Medical Research Institute, Engineering Research Center for Cancer Biomedical and Translational Medicine, Southwest University, Chongqing, China

    Guanghui Zhang & Hongjuan Cui

  5. Department of Pathology, University of Illinois at Chicago, Chicago, IL, USA

    Wancai Yang

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Yang, R., Li, X., Wu, Y. et al. EGFR activates GDH1 transcription to promote glutamine metabolism through MEK/ERK/ELK1 pathway in glioblastoma. Oncogene 39, 2975–2986 (2020). https://doi.org/10.1038/s41388-020-1199-2

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