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Cellular and Molecular Biology

Enhanced nuclear export caused by O-GlcNAcylation of nucleoporins is a potential therapeutic target in mesothelioma

British Journal of Cancer (2026)Cite this article

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Abstract

Background

Mesothelioma is an aggressive malignancy with limited therapeutic options. Genetic alterations involving the Hippo pathway are commonly observed. O-GlcNAcylation is frequently elevated in cancer and drives tumour progression. However, its relationship with Hippo pathway dysfunction in mesothelioma remains unclear.

Methods

O-GlcNAcylation levels were examined in mesothelioma samples and cell lines, and O-GlcNAcylated proteins were detected by mass spectrometry. The functional impact of O-GlcNAcylation was determined by quantifying nuclear transport dynamics using light-induced live-cell imaging. Genetic and pharmacological inhibition of O-GlcNAcylation was evaluated in vitro. Treatment with the nuclear export inhibitor KPT-330 (Selinexor) was assessed in vitro and in a mouse xenograft model.

Results

O-GlcNAcylation was markedly increased in mesothelioma cells with Hippo pathway inactivation. This modification primarily targeted nuclear pore complex proteins, including NUP214 and NUP62, and significantly accelerated nuclear export rates. Suppression of O-GlcNAcylation diminished nuclear export and inhibited cell proliferation. Importantly, pharmacological blockade of nuclear export using KPT-330 suppressed cell growth in vitro and produced significant antitumour effects in vivo.

Conclusions

These findings demonstrate O-GlcNAcylation-driven enhancement of nuclear export as a therapeutically actionable vulnerability in mesothelioma with inactivation of the Hippo pathway.

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Fig. 1: Activation of YAP/TAZ enhanced O-GlcNAcylation in mesothelioma.
Fig. 2: Increased expression of GLUT1 upon YAP/TAZ activation induces O-GlcNAcylation.
Fig. 3: FG-repeats of NUP214 and NUP62 are O-GlcNAcylated sites in mesothelioma cells.
Fig. 4: O-GlcNAcylation accelerates nuclear export in mesothelioma.
Fig. 5: Knockdown of CRM1 suppresses the tumorigenesis of mesothelioma.
Fig. 6: KPT-330 suppresses tumorigenesis in high-O-GlcNAcylated mesotheliomas.

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Data availability

The mass spectrometry proteomics data generated in this study have been deposited to the jPOST repository [48] and are accessible via the ProteomeXchange accession number PXD070876.

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Acknowledgements

We thank Teruaki Fujishita and Masahiro Aoki for technical support and comments on the manuscript. We also thank the Division for Medical Research Engineering, Nagoya University Graduate School of Medicine, for using Q Exactive. We thank Editage for English language editing. This work was supported by JSPS KAKENHI Grant Number JP22H04926, Grant-in-Aid for Transformative Research Areas—Platforms for Advanced Technologies and Research Resources ‘Advanced Bioimaging Support’.

Funding

This work was supported by JSPS KAKENHI (22K07182 (SM), 25K10503 (SM), 24K02336 (YS), and 24K22079 (YS)), Aichi Cancer Research Foundation (SM), Daiko Foundation (SM), Takeda Science Foundation (SM), and Research Grant of the Princess Takamatsu Cancer Research Fund (YS).

Author information

Authors and Affiliations

  1. Division of Cancer Biology, Aichi Cancer Center Research Institute, Nagoya, Japan

    Satomi Mukai, Tatsuhiro Sato, Lisa Kondo-Ida & Yoshitaka Sekido

  2. Optics and Imaging Facility, Trans-Scale Biology Center, National Institute for Basic Biology, National Institutes of Natural Sciences, Okazaki, Japan

    Yasuhiro Kamei & Kagayaki Kato

  3. Basic Biology Program, The Graduate University for Advanced Studies, SOKENDAI, Okazaki, Japan

    Yasuhiro Kamei & Kagayaki Kato

  4. Institute of Transformative Bio-Molecules (WPI-ITbM), Nagoya University, Nagoya, Japan

    Emi Mishiro-Sato

  5. Research Institute for Microbial Diseases, The University of Osaka, Suita, Japan

    Norikazu Yabuta

  6. Department of Pathology, Tokyo Woman’s Medical University Yachiyo Medical Center, Chiba, Japan

    Kenzo Hiroshima

  7. Department of Advanced Biomedical Data Science, Chiba University Graduate School of Medicine, Chiba, Japan

    Kenzo Hiroshima

  8. Department of Cancer Genetics, Nagoya University Graduate School of Medicine, Nagoya, Japan

    Yoshitaka Sekido

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Contributions

SM: Conceptualisation; Formal analysis; Founding acquisition; Investigation; Project acquisition; Validation; Visualisation; Writing—original draft; Writing—review and editing. TS: Resources; Supervision; Writing—review and editing. YK and KK: Methodology; Resources. ES and LI: Investigation. NY: Supervision; Writing—review and editing. KH: Investigation; Resources. YS: Resources; Supervision; Funding acquisition; Writing—review and editing.

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Correspondence to Yoshitaka Sekido.

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The authors declare no competing interests.

Ethics approval and consent to participate

This study was approved by the ethics committee of Aichi Cancer Center (approval number IR041047; approval date, September 2022) and performed in accordance with the Declaration of Helsinki. The requirement for informed consent was waived by the ethics committee because of the minimal risk involved. All animal experiments were performed according to the protocols approved by the Institutional Animal Care and Use Committee of the Aichi Cancer Center.

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Mukai, S., Sato, T., Kamei, Y. et al. Enhanced nuclear export caused by O-GlcNAcylation of nucleoporins is a potential therapeutic target in mesothelioma. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03369-2

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