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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