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Nucleoporin 93, a new substrate of the E3 ubiquitin protein ligase HECTD1, promotes esophageal squamous cell carcinoma progression

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Abstract

Nucleoporin 93 (NUP93) is an important component of the nuclear pore complex, exhibiting pro-tumorigenic properties in some cancers. However, its function in esophageal squamous cell carcinoma (ESCC) has not been elucidated. This study aimed to investigate the effects of NUP93 in ESCC and the underlying mechanisms involved. Through analysis of public human cancer datasets, we observed higher expression of NUP93 in esophageal cancer tissues than in normal tissues. Stable ESCC cell lines with NUP93 overexpression or knockdown were established by lentiviral vector transduction and puromycin selection. NUP93 knockdown suppressed the proliferation, colony formation, cell cycle transition, migration, and invasion of ESCC cells, while the overexpression of NUP93 displayed opposite effects. NUP93 positively regulated epithelial–mesenchymal transition and AKT signaling transduction in ESCC cells. In addition, NUP93 increased the expression of programmed death ligand 1 (PD-L1) in ESCC cells and attenuated NK cell-mediated lysis of ESCC cells. In vivo experiments demonstrated that NUP93 promotes the growth of ESCC in nude mice, enhances Ki67 and PD-L1 expression, and promotes AKT signaling transduction in xenografts. Mechanistically, we demonstrated that the HECT domain E3 ubiquitin protein ligase 1 (HECTD1) contributes to the ubiquitination and degradation of NUP93 and acts as a tumor suppressor in ESCC. To conclude, this study has shown that NUP93 has pro-tumor properties in ESCC and that HECTD1 functions as an upstream regulator of NUP93 in ESCC. These findings may contribute to the investigation of potential therapeutic targets in ESCC.

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The data used and analyzed in the current study are available from the corresponding author upon reasonable request.

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Acknowledgements

This research was funded by the Beijing Medical Award Foundation (No. YXJL-2022-0080-0184).

Funding

This research was funded by the Beijing Medical Award Foundation (No. YXJL-2022–0080-0184).

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Authors and Affiliations

  1. Department of Thoracic Surgery, Esophagus and Mediastinum, Harbin Medical University Cancer Hospital, 150# Haping Road, Harbin, Heilongjiang, China

    Jinfeng Zhang, Yanzhong Xin, Xiaodong Ling, Hao Liang, Luquan Zhang, Chengyuan Fang & Jianqun Ma

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Zhang, J., Xin, Y., Ling, X. et al. Nucleoporin 93, a new substrate of the E3 ubiquitin protein ligase HECTD1, promotes esophageal squamous cell carcinoma progression. Human Cell 37, 245–257 (2024). https://doi.org/10.1007/s13577-023-01005-2

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