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Pleckstrin homology and RhoGEF domain containing G4 (PLEKHG4) leads to the activation of RhoGTPases promoting the malignant phenotypes of thyroid cancer

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Abstract

Thyroid cancer (TC) is one of the most common endocrine system cancers, and its incidence is elevating. There is an urgent need to develop a deeper understanding of TC pathogenesis and explore new therapeutic target for its treatment. This study aimed to investigate the effects of pleckstrin homology and RhoGEF domain containing G4 (PLEKHG4) on the progression of TC. Herein, 29 pairs of TC and adjacent tissues were used to assess the expression of PLEKHG4. A xenograft model of mouse was established by subcutaneously injected with TC cells. Lung metastasis model was established through left ventricular injection. The results revealed that PLEKHG4 was up-regulated in human TC tissues. PLEKHG4 level was correlated with clinicopathological parameters of TC patients. In vitro assays revealed that PLEKHG4 promoted TC cell proliferation, migration, invasion, and epithelial-mesenchymal transformation. Knockdown of PLEKHG4 led to the opposite effects, and the loss of PLEKHG4 enhanced the apoptosis ability and inhibited the stemness properties of TC cells. These findings were further confirmed by the in vivo growth and lung metastasis of TC tumor. Mechanistically, PLEKHG4 promoted the activation of RhoGTPases RhoA, Cdc42, and Rac1. The inhibitors of these RhoGTPases reversed the PLEKHG4-induced malignant phenotypes. Additionally, ubiquitin-conjugating enzyme E2O (UBE2O), a large E2 ubiquitin-conjugating enzyme acted as an ubiquitin enzyme of PLEKHG4, facilitated its ubiquitination and degradation. In conclusion, PLEKHG4, regulated by UBE2O, promoted the thyroid cancer progression via activating the RhoGTPases pathway. UBE2O/PLEKHG4/RhoGTPases axis is expected to be a novel a therapeutic target for TC treatment.

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Data availability

The data used to support the findings of this study are available from the authors on reasonable request.

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Acknowledgements

This research was funded by the Medical Science and Technology Project of Henan Province (No. LHGJ20190150).

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Authors and Affiliations

  1. Department of Thyroid Surgery, The First Affiliated Hospital of Zhengzhou University, 1# Jianshe East Road, Zhengzhou, Henan, China

    Qingling Yuan, Yuxia Fan, Zheng Liu, Xiaoming Wang, Meng Jia, Yongqiang Dong, Zushi Geng, Jian Zheng & Xiubo Lu

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  1. Qingling Yuan
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  8. Jian Zheng
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Contributions

QY, conceptualization, methodology, formal analysis, and writing—original draft; YF, ZL, and XW, conceptualization, validation, and investigation; MJ, YD, ZG, and JZ, conceptualization, formal analysis, and methodology; XL, conceptualization, resources and writing—review & editing. All authors approve the final version of manuscript.

Corresponding authors

Correspondence to Qingling Yuan or Xiubo Lu.

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Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.

Ethical approval

The study was approved by the Life Science Ethics Review Committee of Zhengzhou University in accordance with the Declaration of Helsinki. 29 pairs of TC and adjacent tissues were obtained from The First Affiliated Hospital of Zhengzhou University. Informed consents were obtained from all participates.

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Informed consents were obtained from all individual participants included in the study.

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The authors affirm that human research participants provided informed consent for publication of the images in Figure 3a and Table 2.

Human and animal rights

All animal studies were approved by the Life Science Ethics Review Committee of Zhengzhou University following The Guideline for the Care and Use of Laboratory Animals.

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Yuan, Q., Fan, Y., Liu, Z. et al. Pleckstrin homology and RhoGEF domain containing G4 (PLEKHG4) leads to the activation of RhoGTPases promoting the malignant phenotypes of thyroid cancer. Apoptosis 28, 1315–1331 (2023). https://doi.org/10.1007/s10495-023-01861-1

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