POM121 O-GlcNAcylation facilitates bone metastasis in nonsmall cell lung cancer through enhanced c-MYC nuclear import and ECM reprogramming

Sep 23, 2026

Uploaded by Rhys

Bone metastasis is a devastating complication of non-small cell lung cancer (NSCLC), yet its molecular drivers remain incompletely defined. Comparative analysis between a bone-metastatic NSCLC subpopulation and parental cells identifies elevated OGT and increased O-GlcNAcylation at Ser199 of POM121. Mechanistically, POM121 O-GlcNAcylation weakens TRIM21-mediated ubiquitination, stabilizing POM121 and boosting c-MYC nuclear import, followed by transcriptional activation of ECM-related genes. Clinical data show that OGT, POM121, and c-MYC levels associate with poor outcomes, supporting this axis as diagnostic biomarker and therapeutic target.

LanguageEnglish

CategoryHealthcare

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Pages16

Reading Time40 min

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Introduction

Post-translational modifications and O-GlcNAcylation in cancer

Nuclear pore complexes and the role of POM121

[www.nature.com/onc](www.nature.com/onc Oncogene)[ Oncogene](www.nature.com/onc Oncogene) ARTICLE OPEN POM121 O-GlcNAcylation facilitates bone metastasis in nonsmall cell lung cancer through enhanced c-MYC nuclear import and ECM reprogramming Yi-Zhe Ren 1,3, Ming-Na Zhao 1,3, Feng-Lin Du2, Lei Wu1, Lin Wang 1 ✉ and Jia-Tao Lou 1 ✉ © The Author(s) 2026 | | | | | --- | --- | --- | | | 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. | | | | | Oncogene (2026) 45:728–743; [https://doi.org/10.1038/s41388-026-03687-y](https://doi.org/10.1038/s41388-026-03687-y) | | | | | | INTRODUCTION Non-small cell lung cancer (NSCLC) ranks among malignancies with the highest mortality rates due to metastatic dissemination and limited therapeutic options [1] . Over 70% of patients present with locoregional or distant metastasis at diagnosis [2], with bone being a predominant site that severely compromises quality of life [3] . Notably, 30–40% of NSCLC patients develop bone metastases, correlating with a median survival of only 6 months [4, 5] . Current therapies (bisphosphonates, denosumab) target osteoclastmediated bone destruction but lack tumor-speciﬁc precision [6–8] . Thus, deﬁning molecular drivers of bone metastasis is imperative for developing targeted interventions. Post-translational modiﬁcations (PTMs), including glycosylation, phosphorylation, acetylation, methylation, and palmitoylation, orchestrate cancer hallmarks by modulating protein stability, localization, activity and interactions [9] . Among these PTMs, O-GlcNAcylation has emerged as a critical PTM, wherein dysregulation of its homeostatic balance is implicated in tumor initiation and progression. This nutrient-sensitive PTM dynamically conjugates O-linked N-acetylglucosamine to serine/threonine residues of nuclear, cytoplasmic, and mitochondrial proteins [10, 11] . Its dynamic cycling is exclusively regulated by a binary enzyme system: O-GlcNAc transferase (OGT) for installation and O-GlcNAcase (OGA) for removal [12] . O-GlcNAcylation modulates signaling cascades, protein trafﬁcking and stability, transcriptional programs, epigenetic regulation, mitochondrial dynamics, and cellular survival pathways [13] . Accumulating evidence underscores the critical regulatory roles of O-GlcNAcylation in driving metastasis in cancers. For example, FOXA1 O-GlcNAcylation promotes breast cancer metastasis by stabilizing FOXA1 and orchestrating transcription of metastasis regulators [14

FAQs

What key changes were found in bone-metastatic NSCLC cells?

The study reports elevated OGT expression and markedly increased O-GlcNAcylation of POM121 at the Ser199 site in bone-metastatic NSCLC cells compared with parental counterparts.

How does POM121 O-GlcNAcylation promote bone metastasis mechanistically?

O-GlcNAcylation at Ser199 reduces POM121 interaction with the E3 ubiquitin ligase TRIM21, antagonizing ubiquitination and stabilizing POM121. Stabilized POM121 enhances nuclear import of c-MYC.

Why is the OGT-POM121-c-MYC-ECM axis clinically relevant?

Clinical analysis indicates that high OGT, POM121, and c-MYC levels correlate with adverse outcomes, supporting the axis as a potential diagnostic biomarker and therapeutic target for NSCLC bone metastasis.

Sep 23, 2026

Uploaded by Rhys