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VEZF1, destabilized by STUB1, affects cellular growth and metastasis of hepatocellular carcinoma by transcriptionally regulating PAQR4

Cancer Gene Therapy volume 30, pages 256–266 (2023)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is an aggressive solid malignancy, and recurrence and metastasis are major incentives contributing to its poor outcome. Vascular endothelial zinc finger 1 (VEZF1) has been recognized as an oncoprotein in certain types of cancer, but the expression pattern and regulatory mechanism in HCC remains unclear. This study focused on the functional effect and regulatory basis of VEZF1 in HCC. Microarray analysis identified the differentially expressed VEZF1 in HCC, and we validated its raised expression in HCC clinical samples. Artificial modulation of VEZF1 (knockdown and overexpression) was conducted to explore its role in HCC progression both in vitro and in vivo. It was shown that silencing of VEZF1 suppressed, whereas its overexpression promoted HCC cellular proliferation and metastasis abilities. Mechanistically, VEZF1 transcriptionally activated progestin and adipoQ receptor 4 (PAQR4) to accelerate HCC progression. Furthermore, VEZF1 is confirmed as a substrate of stress-inducible phosphoprotein 1 homology and U-box containing protein 1 (STUB1), and its stability is impacted by STUB1-mediated ubiquitination degradation. Conjointly, our work suggested that VEZF1, destabilized by STUB1, participates in HCC progression by regulating PAQR4. The STUB1/VEZF1/PAQR4 mechanism might provide novel insights on guiding early diagnosis and therapy in HCC patients.

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Fig. 1: VEZF1 is upregulated in human HCC.
Fig. 2: VEZF1 accelerates HCC cell proliferation in vitro.
Fig. 3: VEZF1 promotes HCC cell metastasis in vitro.
Fig. 4: VEZF1 facilitates tumor growth and metastasis in vivo.
Fig. 5: VEZF1 transcriptionally regulates PAQR4 to mediate proliferation and metastasis of HCC.
Fig. 6: U-box domain of STUB1 mediates the ubiquitination and degradation of VEZF1 protein.
Fig. 7: Schematic illustration for the mechanism of STUB1-mediated VEZF1 ubiquitination and subsequent PAQR4 transcriptional activation in HCC.

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Acknowledgements

This research was supported by Beijing Medical Award Foundation (No. HRIRF-2018-C020).

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Authors and Affiliations

  1. Department of Radiology, The Fourth Affiliated Hospital of China Medical University, Shenyang, China

    Xiaobao Shi

  2. Department of Interventional Medicine, Shengjing Hospital of China Medical University, Shenyang, China

    Pengfei Zhao & Gang Zhao

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Contributions

GZ designed the study. XS and PZ were involved in experiments and data collection. XS and GZ performed the statistical analysis and preparation of figures. XS drafted the paper. GZ revised the paper. All authors read and approved the final manuscript.

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Correspondence to Gang Zhao.

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This study was approved by the Ethics Committee of Fourth Affiliated Hospital of China Medical University in accordance with principles of the Helsinki Declaration. Informed consent of all subjects was received. Animal experiments were approved by the Experimental Animal Ethics Committee of Fourth Affiliated Hospital of China Medical University. All efforts were made to relief the suffering of animals.

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Shi, X., Zhao, P. & Zhao, G. VEZF1, destabilized by STUB1, affects cellular growth and metastasis of hepatocellular carcinoma by transcriptionally regulating PAQR4. Cancer Gene Ther 30, 256–266 (2023). https://doi.org/10.1038/s41417-022-00540-8

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