[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-448516-105":59,"doc-detail-448516-en":123},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":116,"head_meta":118,"extra_data":120,"updated_unix":122},105,"en","targeting-the-mettl3pcna-axis-with-stm2457-overcomes-cisplatin-resistance-in-osteosarcoma","Targeting the METTL3/PCNA axis with STM2457 - Overcomes cisplatin resistance in osteosarcoma","","Cisplatin resistance is a major clinical barrier in osteosarcoma, with complex molecular causes that remain incompletely understood. This study evaluates how the RNA methyltransferase METTL3 and m6A modification regulate cisplatin resistance through the METTL3-m6A-PCNA axis. Using cisplatin-resistant OS cell lines, the selective METTL3 inhibitor STM2457 suppresses proliferation and migration and strengthens cisplatin-induced apoptosis. Mechanistically, STM2457 reduces global m6A and destabilizes PCNA mRNA, lowering PCNA protein; PCNA knockdown mimics, while PCNA overexpression partially restores, the resistant phenotype.",{"@graph":69,"@context":115},[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/targeting-the-mettl3pcna-axis-with-stm2457-overcomes-cisplatin-resistance-in-osteosarcoma/448516/",{"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/targeting-the-mettl3pcna-axis-with-stm2457-overcomes-cisplatin-resistance-in-osteosarcoma/448516.png","ImageObject",300,407,{"name":92,"@type":93},"Jake","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-09","2026-09-30",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109],{"name":110,"@type":111,"acceptedAnswer":112},"How were PCNA causal effects tested in the study?","Question",{"text":113,"@type":114},"PCNA knockdown mimicked STM2457’s anti-tumor effects, while PCNA overexpression attenuated STM2457 efficacy and partially restored the cisplatin-resistant phenotype.","Answer","https://schema.org",{"og:url":83,"og:type":117,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":119,"canonical":83},"index,follow",{"doc_id":121,"site_id":62},448516,1790849983,{"code":4,"msg":5,"data":124},{"doc_id":121,"user_id":125,"nickname":92,"user_avatar":126,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":127,"file_id":128,"file_url":129,"file_type":130,"file_size":131,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":105,"language":132,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":133,"faqs":134,"seo_title":135,"seo_description":67,"update_tm":136,"read_time":41,"preview_page_count":4},962084928904,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Targeting the METTL3/PCNA axis with STM2457 overcomescisplatin resistance in osteosarcoma  \nHua Yu1\\#, Shaoxing Li2\\#, Jinwang Liu1  \n1Department of Orthopedics, the First Affiliated Hospital of Chengdu Medical College, Chengdu, China; 2Department of Gynaecology and Obstetrics, the First Affiliated Hospital of Chengdu Medical College, Chengdu, China  \nContributions: (I) Conception and design: H Yu, S Li; (II) Administrative support: J Liu; (III) Provision of study materials or patients: None; (IV) Collection and assembly of data: H Yu, S Li; (V) Data analysis and interpretation: All authors; (VI) Manuscript writing: All authors; (VII) Final  \napproval of manuscript: All authors.  \n\\#These authors contributed equally to this work.  \nCorrespondence to: Jinwang Liu, PhD. Department of Orthopedics, the First Affiliated Hospital of Chengdu Medical College, 278 Baoguang Avenue, Xindu District, Chengdu 610500, China. Email: [liujinwang1984@163.com](liujinwang1984@163.com).  \nBackground: Cisplatin resistance represents a major clinical challenge in osteosarcoma (OS), often leading to treatment failure and poor patient prognosis. The underlying molecular mechanisms are complex and incompletely understood. This study investigates the role of the RNA methyltransferase methyltransferaselike 3 (METTL3) and its associated N6-methyladenosine (m6A) modification in driving cisplatin resistance, with a specific focus on the METTL3-m6A-proliferating cell nuclear antigen (PCNA) regulatory axis as a  \npotential therapeutic target.  \nMethods: Cisplatin-resistant human OS cell lines (MG-63/DDP, U2OS/DDP) were used. The effects of the selective METTL3 inhibitor STM2457, both alone and in combination with cisplatin, on cell viability, apoptosis, and migration were evaluated using Cell Counting Kit-8 (CCK-8) assay, immunofluorescence staining for cleaved Caspase-3, and vimentin expression, respectively. Mechanistic investigations included quantification of global m6A levels, analysis of PCNA messenger RNA (mRNA) stability via actinomycin Dassay, and western blot for protein expression. Functional roles were validated using small interfering RNAmediated PCNA knockdown and plasmid-based PCNA overexpression. Drug interaction was analyzed using  \nthe combination index (CI) method.  \nResults: STM2457 monotherapy significantly and dose-dependently suppressed cell proliferation and migration in cisplatin-resistant OS cells. Furthermore, STM2457 demonstrated strong synergistic effects with cisplatin (CI \u003C1), markedly enhancing apoptosis induction. At the molecular level, STM2457 inhibited METTL3 catalytic activity, leading to a significant reduction in global m6A RNA methylation. This resulted in the destabilization of PCNA mRNA and a consequent decrease in PCNA protein levels. Knockdown of PCNA effectively mimicked the anti-tumor effects of STM2457, whereas forced overexpression of PCNA  \nattenuated the efficacy of STM2457 and partially restored the cisplatin-resistant phenotype.  \nConclusions: Our findings demonstrate that STM2457 overcomes cisplatin resistance in OS by targeting the METTL3-m6A-PCNA axis, thereby disrupting a key DNA repair and cell survival pathway.  \nPharmacological inhibition of METTL3 represents a novel and promising epigenetic strategy for  \nresensitizing chemoresistant OS, supporting its potential for future clinical development.  \nKeywords: Methyltransferase-like 3 (METTL3); STM2457; cisplatin resistance; osteosarcoma (OS); proliferating  \ncell nuclear antigen (PCNA)  \nSubmitted Jul 02, 2025. Accepted for publication Oct 22, 2025. Published online Dec 05, 2025.  \ndoi: 10.21037/tcr-2025-1429  \nView this article at: [https://dx.doi.org/10.21037/tcr-2025-1429](https://dx.doi.org/10.21037/tcr-2025-1429)  \n© AME Publishing Company. Transl Cancer Res 2025;14(12):8567-8578 | [https://dx.doi.org/10.21037/tcr-2025-1429](https://dx.doi.org/10.21037/tcr-2025-1429)  \n8568 Yu et al. STM2457 overcomes cisplatin resistance in OS  \nIntroduction  \nOst","cbCaikuB10a2lG3c","https://ap.wps.com/l/cbCaikuB10a2lG3c","pdf",844929,"English","# Introduction\n## Cisplatin resistance in osteosarcoma and PCNA\n## METTL3-mediated m6A as a therapeutic axis\n# Methods\n## Cell models and treatments\n## Functional and mechanistic assays\n# Results\n## STM2457 inhibits growth and migration\n## Synergy with cisplatin and apoptosis effects\n## METTL3 inhibition, m6A reduction, and PCNA regulation\n# Conclusions\n## Therapeutic implication of STM2457 targeting METTL3-m6A-PCNA axis\n# Key findings","[{\"question\":\"How were PCNA causal effects tested in the study?\",\"answer\":\"PCNA knockdown mimicked STM2457’s anti-tumor effects, while PCNA overexpression attenuated STM2457 efficacy and partially restored the cisplatin-resistant phenotype.\"}]","Targeting the METTL3/PCNA axis with STM2457 - Overcomes cisplatin resistance in osteosarcoma | PDF",1790727516]