Bone metastasis is a devastating complication of non-small cell lung cancer (NSCLC), critically impairing patient survival. Nevertheless, the underlying molecular mechanisms driving this aggressive process remain incompletely elucidated. To systematically investigate these mechanisms, we compared a highly bone-metastatic NSCLC subpopulation with its parental cells. Notably, we identified elevated expression of O-linked β-N-acetylglucosamine transferase (OGT) in the metastatic subpopulation. We further demonstrated that O-GlcNAcylation at the Ser199 site of the nuclear pore protein POM121 is markedly increased and drives NSCLC bone metastasis. Mechanistically, O-GlcNAcylation of POM121 attenuates its interaction with the E3 ubiquitin ligase TRIM21, thus antagonizing ubiquitination and stabilizing POM121. Accumulated POM121 enhances the nuclear import of the oncogenic transcription factor c-MYC. Nuclear c-MYC subsequently orchestrates transcriptional activation of downstream extracellular matrix (ECM)-related genes. Collectively, we elucidate a previously unrecognized OGT-POM121-c-MYC-ECM axis that critically drives NSCLC bone metastasis. Crucially, clinical analysis reveals that high levels of OGT, POM121, and c-MYC positively correlate with adverse clinical outcomes. These findings establish the OGT-POM121-c-MYC-ECM axis as a potential diagnostic biomarker and a promising therapeutic target for NSCLC bone metastasis.
Ren et al. (Mon,) studied this question.