[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-384110-105":59,"doc-detail-384110-en":129},{"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":122,"head_meta":124,"extra_data":126,"updated_unix":128},105,"en","usp39-promotes-hepatocellular-carcinogenesis-through-regulating-alternative-splicing-in-cooperation-with-srsf6hnrnpc","USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC","","Aberrant alternative splicing driven by spliceosomal alterations contributes to cancer biology, yet how mid/late spliceosome factors shape tumor splice-site choice remains unclear. USP39 is shown to enhance hepatocarcinogenesis via splice-site selection in hepatocyte-specific USP39 transgenic mice and to promote proliferation in a spliceosome-dependent manner in human liver cancer cells. USP39 loss deregulates hundreds of splicing events, including oncogenic KANK2 splice switching. Mechanistically, USP39 regulates exon inclusion/exclusion by cooperating with SRSF6/HNRNPC, supported by RBP-motif enrichment analysis, establishing a control paradigm and potential biomarker targets.",{"@graph":69,"@context":121},[70,84,104],{"@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/usp39-promotes-hepatocellular-carcinogenesis-through-regulating-alternative-splicing-in-cooperation-with-srsf6hnrnpc/384110/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":98,"encodingFormat":97,"isAccessibleForFree":99,"interactionStatistic":100},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/usp39-promotes-hepatocellular-carcinogenesis-through-regulating-alternative-splicing-in-cooperation-with-srsf6hnrnpc/384110.png","ImageObject",300,407,{"name":92,"@type":93},"McQueen","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-24",true,{"@type":101,"interactionType":102,"userInteractionCount":8},"InteractionCounter",{"@type":103},"ViewAction",{"@type":105,"mainEntity":106},"FAQPage",[107,113,117],{"name":108,"@type":109,"acceptedAnswer":110},"What is the main focus of this article?","Question",{"text":111,"@type":112},"The article investigates how USP39, a mid/late-acting spliceosome component, regulates alternative splicing to drive hepatocellular carcinogenesis, and how it cooperates with SRSF6/HNRNPC to control splice-site choice.","Answer",{"name":114,"@type":109,"acceptedAnswer":115},"How does USP39 affect hepatocarcinogenesis in vivo and in human cancer cells?",{"text":116,"@type":112},"Hepatocyte-specific USP39 overexpression promotes hepatocarcinogenesis in transgenic mice, and USP39 enhances tumor proliferation in human liver cancer cells in a spliceosome-dependent manner.",{"name":118,"@type":109,"acceptedAnswer":119},"What happens to alternative splicing when USP39 is depleted?",{"text":120,"@type":112},"USP39 depletion deregulates hundreds of alternative splicing events, including an oncogenic splice-switching event in KANK2.","https://schema.org",{"og:url":83,"og:type":123,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":125,"canonical":83},"index,follow",{"doc_id":127,"site_id":62},384110,1790293159,{"code":4,"msg":5,"data":130},{"doc_id":127,"user_id":131,"nickname":92,"user_avatar":132,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":133,"file_id":134,"file_url":135,"file_type":136,"file_size":137,"view_count":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":138,"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},5909890329169,"https://ap-avatar.wpscdn.com/davatar_9964176cb1d06d4a9deccf72a44ae3dc","[www.nature.com/cddis](www.nature.com/cddis)  \nARTICLE OPEN   \nUSP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC  \nJingyi Zheng 1,4, Shasha Wu1,4, Mao Tang 1, Shaoyan Xi2,3, Yanchen Wang 1, Jun Ren 1, Hao Luo1, Pengchao Hu 1, Liangzhan Sun1, Yuyang Du 1, Hui Yang1, Fenfen Wang 1, Han Gao 1, Ziwei Dai1, Xijun Ou 1 and Yan Li 1 ✉  \n© The Author(s) 2023  \n|  |  |  |\n| --- | --- | --- |\n|  | Abnormal alternative splicing (AS) caused by alterations in spliceosomal factors is implicated in cancers. Standard models posit that splice site selection is mainly determined by early spliceosomal U1 and U2 snRNPs. Whether and how other mid/late-acting spliceosome components such as USP39 modulate tumorigenic splice site choice remains largely elusive. We observed that hepatocyte-specific overexpression of USP39 promoted hepatocarcinogenesis and potently regulated splice site selection in transgenic mice. In human liver cancer cells, USP39 promoted tumor proliferation in a spliceosome-dependent manner. USP39 depletion deregulated hundreds of AS events, including the oncogenic splice-switching of KANK2 . Mechanistically, we developed a novel RBP-motif enrichment analysis and found that USP39 modulated exon inclusion/exclusion by interacting with SRSF6/HNRNPC in both humans and mice. Our data represented a paradigm for the control of splice site selection by mid/late-acting spliceosome proteins and their interacting RBPs. USP39 and possibly other mid/late-acting spliceosome proteins may represent potential |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| prognostic biomarkers and targets for cancer therapy. |  |  |\n|  | Cell Death and Disease (2023)14:670; [https://doi.org/10.1038/s41419-023-06210-3](https://doi.org/10.1038/s41419-023-06210-3) |  |\n|  |  |  |\n\nINTRODUCTION  \nAlternative splicing (AS) is an important mechanism of RNA processing that generates different mRNA/protein isoforms from a single mRNA transcript, thereby enlarging the diversity and complexity of the transcriptome and proteome. Pre-mRNA splicing is carried out by the spliceosome, a megadalton complex comprising five small nuclear ribonucleoprotein particles (U1, U2, U4/5/6 snRNP) and over 100 core set proteins. The key to AS regulation lies in the selection of splice sites, which is believed tobe mainly determined by U1 and U2 snRNPs, due to their direct recognition of 5’/3’ splice sites. Additional interactions that regulate splice site selection are mediated by RBPs (e.g., SR and hnRNP protein families), which recognize auxiliary sequences in the pre-mRNA to promote or inhibit complex A assembly. Subsequent binding of preassembled U4/5/6 tri-snRNP forms complex B, which undergoes a series of conformational changes to form complexes Bact and C, and concomitantly carries out the two trans-esterification reactions to generate splicing intermediates and products [1] .  \nOver the past decade, rapid developments in high-throughput technologies have revealed broad alterations in splicing in various cancers [2–4] . Genetic alteration and/or abnormal expression of spliceosomal components have been frequently detected and contribute to the abnormal splicing patterns in tumors. These  \nfindings indicate that cancer-related isoforms and various splicing regulatory factors can be used as potential targets in cancer therapy, leading to a new treatment strategy called spliceosometargeted therapies [5–7] . U1 and U2 snRNP components have been intensively studied and pharmacologically targeted because of their direct influence on splice site recognition and frequent mutation in hematological tumors [8, 9]. Small molecules targeting these components, such as SF3B inhibitors, cause severe toxic side effects due to their general regulation of splicing efficiency, although they are effective in various cancers [10] . On the other hand, targeting non-spliceosomal regulators","cbCaijPAbMwpDDaa","https://ap.wps.com/l/cbCaijPAbMwpDDaa","pdf",7027355,14,"English","# Introduction\n## Alternative splicing and spliceosome regulation\n## Cancer-associated splicing alterations and therapeutic implications\n## Mid- and late-acting spliceosome components as targets\n## USP39 as a case study","[{\"question\":\"What is the main focus of this article?\",\"answer\":\"The article investigates how USP39, a mid/late-acting spliceosome component, regulates alternative splicing to drive hepatocellular carcinogenesis, and how it cooperates with SRSF6/HNRNPC to control splice-site choice.\"},{\"question\":\"How does USP39 affect hepatocarcinogenesis in vivo and in human cancer cells?\",\"answer\":\"Hepatocyte-specific USP39 overexpression promotes hepatocarcinogenesis in transgenic mice, and USP39 enhances tumor proliferation in human liver cancer cells in a spliceosome-dependent manner.\"},{\"question\":\"What happens to alternative splicing when USP39 is depleted?\",\"answer\":\"USP39 depletion deregulates hundreds of alternative splicing events, including an oncogenic splice-switching event in KANK2.\"}]","USP39 promotes hepatocellular carcinogenesis through regulating alternative splicing in cooperation with SRSF6/HNRNPC | PDF",1790261265,35]