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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.",{"@graph":69,"@context":123},[70,84,106],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/pom121-o-glcnacylation-facilitates-bone-metastasis-in-nonsmall-cell-lung-cancer-through-enhanced-c-myc-nuclear-import-and-ecm-reprogramming/362374/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/pom121-o-glcnacylation-facilitates-bone-metastasis-in-nonsmall-cell-lung-cancer-through-enhanced-c-myc-nuclear-import-and-ecm-reprogramming/362374.png","ImageObject",300,407,{"name":92,"@type":93},"Rhys","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-30","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What key changes were found in bone-metastatic NSCLC cells?","Question",{"text":113,"@type":114},"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.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does POM121 O-GlcNAcylation promote bone metastasis mechanistically?",{"text":118,"@type":114},"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.",{"name":120,"@type":111,"acceptedAnswer":121},"Why is the OGT-POM121-c-MYC-ECM axis clinically relevant?",{"text":122,"@type":114},"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.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},362374,1790643428,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":36},687207024643,"https://ap-avatar.wpscdn.com/davatar_3d24733baf745e90a7e4bdd5f77d97b2","[www.nature.com/onc](www.nature.com/onc Oncogene)[ Oncogene](www.nature.com/onc Oncogene)  \nARTICLE OPEN   \nPOM121 O-GlcNAcylation facilitates bone metastasis in nonsmall cell lung cancer through enhanced c-MYC nuclear import and ECM reprogramming  \nYi-Zhe Ren 1,3, Ming-Na Zhao 1,3, Feng-Lin Du2, Lei Wu1, Lin Wang 1 ✉ and Jia-Tao Lou 1 ✉  \n© The Author(s) 2026  \n|  |  |  |\n| --- | --- | --- |\n|  | 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 |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| biomarker and a promising therapeutic target for NSCLC bone metastasis. |  |  |\n|  | Oncogene (2026) 45:728–743; [https://doi.org/10.1038/s41388-026-03687-y](https://doi.org/10.1038/s41388-026-03687-y) |  |\n|  |  |  |\n\nINTRODUCTION  \nNon-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.  \nPost-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  \nprograms, 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","cbCaiiupW3Gkhwri","https://ap.wps.com/l/cbCaiiupW3Gkhwri","pdf",3897341,16,"English","# Introduction\n## Post-translational modifications and O-GlcNAcylation in cancer\n## Nuclear pore complexes and the role of POM121","[{\"question\":\"What key changes were found in bone-metastatic NSCLC cells?\",\"answer\":\"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.\"},{\"question\":\"How does POM121 O-GlcNAcylation promote bone metastasis mechanistically?\",\"answer\":\"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.\"},{\"question\":\"Why is the OGT-POM121-c-MYC-ECM axis clinically relevant?\",\"answer\":\"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.\"}]","POM121 O-GlcNAcylation facilitates bone metastasis in nonsmall cell lung cancer through enhanced c-MYC nuclear import and ECM reprogramming | PDF",1790147443]