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This study shows that high COP9 signalosome subunit 6 (CSN6) expression in PDAC correlates with poor prognosis and gemcitabine resistance. Conditional CSN6 knockout suppresses tumor formation in a spontaneous PDAC mouse model. Mechanistically, CSN6 activates ribosome biogenesis by antagonizing DCAF1-mediated ubiquitination of NPM1, enhancing translation of gemcitabine-resistance genes. Combining gemcitabine with the NPM1 inhibitor NSC348884 synergistically suppresses CSN6-high xenografts.",{"@graph":69,"@context":122},[70,84,105],{"@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":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/csn6-promotes-pancreatic-cancer-progression-and-gemcitabine-resistance-via-antagonizing-dcaf1-mediated-ubiquitination-of-npm1-research-article/439694/",{"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/csn6-promotes-pancreatic-cancer-progression-and-gemcitabine-resistance-via-antagonizing-dcaf1-mediated-ubiquitination-of-npm1-research-article/439694.png","ImageObject",300,407,{"name":92,"@type":93},"Rizky","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-02","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What relationship exists between CSN6 expression and PDAC outcomes?","Question",{"text":112,"@type":113},"High CSN6 levels in PDAC tumors associate with poor prognosis, and CSN6 expression correlates positively with NPM1. Concurrent high expression is linked to significantly worse clinical outcomes.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does CSN6 contribute to gemcitabine resistance?",{"text":117,"@type":113},"CSN6 antagonizes DCAF1-mediated ubiquitination of NPM1, promoting NPM1-driven ribosome biogenesis. This increases translation of gemcitabine resistance genes such as CDA and RRM1/2.",{"name":119,"@type":110,"acceptedAnswer":120},"What evidence supports CSN6 as an oncogenic driver in PDAC?",{"text":121,"@type":113},"Conditional knockout of CSN6 hinders tumor formation in a spontaneous PDAC mouse model. Proteomic analysis indicates CSN6 promotes ribosome biogenesis via activation of rDNA transcription and protein synthesis.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},439694,1790878085,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":56,"language":139,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":140,"faqs":141,"seo_title":142,"seo_description":67,"update_tm":143,"read_time":144},962085564807,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nCSN6 Promotes Pancreatic Cancer Progression and Gemcitabine Resistance via Antagonizing DCAF1-Mediated Ubiquitination ofNPM1  \nYijing Zhang, Han Gao, Aiwen Tang, Haiwen Lyu, Zongmin Fan, Jiahui Guo, Yuzhi Wang, Hairong Yi, Qihao Pan, Haidan Luo, Baifu Qin, Boyu Zhang, Xiangqi Meng, Qingxin Liu, and Mong-Hong Lee*  \nPancreatic ductal adenocarcinoma (PDAC) is a fatal cancer with poor prognosis. COP9 signalosome subunit 6 (CSN6), a key regulator of different E3 ubiquitin ligases, plays oncogenic roles in various cancers. However, its function in PDAC remains elusive. Here, this demonstrates that human PDAC tumors expressing high levels of CSN6 present with poor prognosis and gemcitabine resistance. Conditional knockout (KO) of CSN6 hinders tumor formation in a KPP spontaneous PDAC mouse model. Proteomic analysis indicates that CSN6 promotes ribosome biogenesis by activating rDNA transcription and protein synthesis. Mechanistically, CSN6 antagonizes DDB1-CUL4 associated factor 1 (DCAF1)-mediated ubiquitination of Nucleophosmin (NPM1), thereby promoting NPM1-orchestrated ribosome biogenesis. In line with CSN6-mediated gemcitabine resistance, CSN6-NPM1 axis enhances ribosome biogenesis, thereby promoting translation of gemcitabine resistance genes, including Cytidine deaminase (CDA), Ribonucleotide reductase subunit M1/2 (RRM1/2). Significantly, combining gemcitabine with NPM1 inhibitor NSC348884 synergistically suppresses CSN6-high pancreatic cancer xenografts. Clinically, CSN6 expression positively correlates with NPM1 in PDAC tissues, and their concurrent high expression is significantly associated with poor clinical outcomes. This study characterizes CSN6 as an oncogenic protein that promotes NPM1 stabilization by interacting with DCAF1, thereby enhancing ribosome biogenesis and cellular resistance to gemcitabine in PDAC. NPM1 may serve as a therapeutic target for CSN6 high PDAC that exhibits gemcitabine drug resistance.  \n1. Introduction  \nPancreatic ductal adenocarcinoma (PDAC) is recognized as one of the most lethal and highly aggressive cancers with limited treatment options. [1] Gemcitabine, a nucleoside analog, has been applied in the treatment of pancreatic ductal adenocarcinoma. [2,3] However, intrinsic or acquired resistance compromises the therapeutic potential of gemcitabine and is the major impediment to achieving expected clinical outcomes. [4] Comprehensive genetic and proteomic characterization of PDAC holds promise for developing more effective treatment strategies. [5] Also, to propose new treatment options for the large majority of advanced PDAC patients who will face gemcitabine resistance, it has become mandatory to better understand the mechanisms of acquired gemcitabine resistance.  \nThe constitutive photomorphogenesis 9 (COP9) signalosome (CSN) is a highly conserved protein complex present from plants to humans. It functioning as a key regulator in ubiquitin-mediated protein degradation pathway and participates in diverse biological processes, including signal transduction, cell cycle progression, DNA damage response, and tumorigenesis. [6,7] COP9  \nY. Zhang, H. Gao, A. Tang, H. Lyu, Z. Fan, J. Guo, Y. Wang, H. Yi, Q. Pan, H. Luo, B. Zhang, X. Meng, Q. Liu, M.-H. Lee  \nGuangdong Provincial Key laboratory of Colorectal and Pelvic Floor Diseases  \nThe Sixth Affiliated Hospital Sun Yat-sen University Guangzhou 510655, China  \nE-mail: [limh33@mail.sysu.edu.cn](limh33@mail.sysu.edu.cn)  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202510210](https://doi.org/10.1002/advs.202510210)[ ](https://doi.org/10.1002/advs.202510210)© 2025 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is p","cbCaij1flUgkyX6f","https://ap.wps.com/l/cbCaij1flUgkyX6f","pdf",19140852,"English","# 1. Introduction\n## Pancreatic ductal adenocarcinoma and gemcitabine resistance\n## COP9 signalosome and CSN6 in cancer\n## NPM1 and ribosome biogenesis","[{\"question\":\"What relationship exists between CSN6 expression and PDAC outcomes?\",\"answer\":\"High CSN6 levels in PDAC tumors associate with poor prognosis, and CSN6 expression correlates positively with NPM1. Concurrent high expression is linked to significantly worse clinical outcomes.\"},{\"question\":\"How does CSN6 contribute to gemcitabine resistance?\",\"answer\":\"CSN6 antagonizes DCAF1-mediated ubiquitination of NPM1, promoting NPM1-driven ribosome biogenesis. This increases translation of gemcitabine resistance genes such as CDA and RRM1/2.\"},{\"question\":\"What evidence supports CSN6 as an oncogenic driver in PDAC?\",\"answer\":\"Conditional knockout of CSN6 hinders tumor formation in a spontaneous PDAC mouse model. Proteomic analysis indicates CSN6 promotes ribosome biogenesis via activation of rDNA transcription and protein synthesis.\"}]","CSN6 Promotes Pancreatic Cancer Progression and Gemcitabine Resistance via Antagonizing DCAF1-Mediated Ubiquitination of NPM1 - Research Article | PDF",1790689920,48]