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GPER-mediated stabilization of HIF-1α contributes to upregulated aerobic glycolysis in tamoxifen-resistant cells

Oncogene volume 42, pages 184–197 (2023)Cite this article

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Abstract

Tamoxifen is a first-line therapeutic drug for oestrogen-receptor positive breast cancer; however, like other therapeutics, its clinical use is limited by acquired resistance. Tamoxifen-resistant cells have demonstrated enhanced aerobic glycolysis; however, the mechanisms underlying this upregulation remain unclear. Here, we demonstrated that G-protein coupled oestrogen receptor (GPER) was involved in the upregulation of aerobic glycolysis via induction of hypoxia-inducible factor-1α (HIF-1α) expression and transcriptional activity in tamoxifen-resistant cells. Additionally, GPER stabilized HIF-1α through inhibiting its hydroxylation and ubiquitin-mediated degradation, which were associated with upregulation of C-terminal hydrolase-L1 (UCH-L1), downregulation of prolyl hydroxylase 2 (PHD2) and von Hippel-Lindau tumour suppressor protein (pVHL), induction of HIF-1α/UCH-L1 interaction, and suppression of HIF-1α/PHD2-pVHL association. The GPER/HIF-1α axis was functionally responsible for regulating tamoxifen sensitivity both in vitro and in vivo. Moreover, there was a positive correlation between GPER and HIF-1α expression in clinical breast cancer tissues, and high levels of GPER combined with nuclear HIF-1α indicated poor overall survival. High levels of the GPER/HIF-1α axis were also correlated with shorter relapse-free survival in patients receiving tamoxifen. Hence, our findings support a critical role of GPER/HIF-1α axis in the regulation of aerobic glycolysis in tamoxifen-resistant cells, offering a potential therapeutic target for tamoxifen-resistant breast cancer.

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Fig. 1: GPER is required for glycolysis in tamoxifen-resistant breast cancer cells.
Fig. 2: GPER mediates glycolysis via upregulation of HIF-1α expression and transcriptional activity.
Fig. 3: GPER increases HIF-1α protein stability by suppressing ubiquitin degradation.
Fig. 4: GPER enhances HIF-1α/UCH-L1 interaction and suppressed HIF-1α/PHD2-pVHL interaction.
Fig. 5: GPER/HIF-1α axis is involved in regulating tamoxifen resistance.
Fig. 6: GPER/HIF-1α axis is involved in tamoxifen resistance in vivo.
Fig. 7: Positive correlation between GPER and HIF-1α.
Fig. 8: Schematic diagram of GPER/HIF-1α axis in upregulated aerobic glycolysis in tamoxifen-resistant cells.

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Data availability

The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

This work was financially supported by the National Natural Science Foundation of China (81860648, 81973341), the Excellent Young Talents Plan of Guizhou Province (QKHPTRC(2021)-5632), the Guizhou Provincial Science and Technology Projects (QKHJC-ZK(2021)-YB527), the Excellent Young Talents Plan of Guizhou Medical University (2020-101), the Science and Technology Innovation Fund for Advanced Individuals of the Guizhou Department of Education (QJHKY[2018]048), and the Science Foundation of Administration of Traditional Chinese Medicine of Guizhou Province (QZYY-2022-025).

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  1. These authors contributed equally: Yue Zhang, Yuxuan Song, Shuang Ren, Minqin Zhang.

Authors and Affiliations

  1. The High Efficacy Application of Natural Medicinal Resources Engineering Center of Guizhou Province, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China

    Yue Zhang, Yuxuan Song, Shuang Ren, Minqin Zhang, Shuangqin Fan, Xing Liu, Xiaoyu Peng, Xiangchun Shen & Yan Chen

  2. Translational Medicine Research Center of Guizhou Medical University, Guizhou Medical University, University Town, Guian New District, Guiyang, 550025, Guizhou, China

    Yuxuan Song, Shuang Ren, Minqin Zhang, Shuangqin Fan, Xing Liu, Xiaoyu Peng, Xiangchun Shen & Yan Chen

  3. The Key Laboratory of Environmental Pollution Monitoring and Disease Control, Ministry of Education, School of Public Health, Guizhou Medical University, Guiyang, 550025, Guizhou, China

    Yuxuan Song, Shuang Ren, Minqin Zhang, Shuangqin Fan, Xing Liu, Xiaoyu Peng, Xiangchun Shen & Yan Chen

  4. Medical Examination Center, Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, 200021, China

    Zhao Zhang

  5. MOE Key Laboratory of Tumor Molecular Biology, Clinical Translational Center for Targeted Drug, Department of Pharmacology, School of Medicine, Jinan University, Guangzhou, 510632, China

    Qi Qi

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Contributions

YZ, YxS, SR and MqZ were responsible for designing the protocols, performing the experiments and writing the manuscript. ZZ was responsible for extracting and analysing data. SqF contributed to performing the experiments. XL contributed to interpreting results. XyP contributed to writing and revising the manuscript. QQ was responsible for drafting and revising the manuscript. XcS was responsible for approving the final version. YC was responsible for conceiving and designing the work that led to the submission, acquired data, played an important role in interpreting the results, and provided the funding resources.

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Zhang, Y., Song, Y., Ren, S. et al. GPER-mediated stabilization of HIF-1α contributes to upregulated aerobic glycolysis in tamoxifen-resistant cells. Oncogene 42, 184–197 (2023). https://doi.org/10.1038/s41388-022-02506-4

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