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SKP2, an E3 ubiquitin ligase component, drives proteasome-mediated protein degradation and alters substrate functions by attaching K48- or K63-linked ubiquitin chains. Overexpression of SKP2 across cancer types correlates with unfavorable clinical outcomes. Evidence extends SKP2 roles to metabolism, DNA repair, stemness, the tumor microenvironment, and immunotherapy response, supporting SKP2 as an intervention target. This review details SKP2 oncogenic mechanisms and outlines future directions for SKP2-targeted therapy.",{"@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":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/skp2-in-cancer-from-molecular-regulation-to-therapeutic-vulnerabilities-and-translational-perspectives/349518/",{"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/skp2-in-cancer-from-molecular-regulation-to-therapeutic-vulnerabilities-and-translational-perspectives/349518.png","ImageObject",300,407,{"name":92,"@type":93},"kopisore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-31","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":52},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does the ubiquitin-proteasome system (UPS) play in cells, according to the review?","Question",{"text":112,"@type":113},"The UPS regulates intracellular protein homeostasis by covalently labeling proteins with ubiquitin for subsequent degradation. This process depends on E1, E2, and E3 enzymes, which control protein stability and activity in eukaryotic cells.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does SKP2 contribute to cancer progression?",{"text":117,"@type":113},"SKP2, as an E3 ubiquitin ligase, can induce proteasome-mediated degradation or modulate substrate functions by binding K48- or K63-linked ubiquitin chains to targets. Overexpression in multiple cancers is associated with poor clinical outcomes and chemoresistance acquisition.",{"name":119,"@type":110,"acceptedAnswer":120},"What expanded functions of SKP2 are highlighted beyond cell cycle control?",{"text":121,"@type":113},"The review notes emerging evidence that SKP2 also impacts metabolism, DNA repair, stemness, the tumor microenvironment (TME), and immunotherapy response. These findings support SKP2 as an increasingly attractive therapeutic target.","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},349518,1790510505,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":52,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":26},962090880963,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Drug Design, Development and Therapy  \n Open Access Full Text Article  \nREVIEW  \nSKP2 in Cancer: From Molecular Regulation to Therapeutic Vulnerabilities and Translational Perspectives  \nSheng-An Zheng 1 , 2 , *, Cheng Wang 1 , 3 , *, Xiao-Die Yao2 , Jia-Jia Sheng 1 , 2 , Po-Wu Liu 1 , Ying Wang2 , Shi-Jia Deng 1 , He Li 1 ,4 , *  \n1Center for Clinical Investigation, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University/Hunan Cancer Hospital, Changsha, Hunan, 410013, People’s Republic of China; 2School of Pharmacy, Dali University, Dali, Yunnan, 671000, People’s Republic of China; 3Department of Preventive Medicine, Medical School, Hunan University of Chinese Medicine, Changsha, Hunan, 410208, People’s Republic of China; 4Hunan Provincial Key Laboratory of the Research and Development of Novel Pharmaceutical Preparations, The “Double-First Class” Application Characteristic Discipline of Hunan Province (Pharmaceutical Science), Changsha Medical University, Changsha, Hunan, 410219, People’s Republic of China  \n*These authors contributed equally to this work  \nCorrespondence: Shi-Jia Deng; He Li, Email [dengshijia@hnca.org.cn](dengshijia@hnca.org.cn); [lihe@hnca.org.cn](lihe@hnca.org.cn)  \n\n| Abstract: The ubiquitin-proteasome system (UPS) plays a central role in regulating protein homeostasis and degradation. Its dysregulation is closely associated with various diseases, including cancer. S-phase kinase-associated protein 2 (SKP2) is a key E3 ubiquitin ligase component of the UPS. It induces proteasome-mediated protein degradation or modulates substrate function by conjugating K48-linked or K63-linked ubiquitin chains to diverse target proteins. Recent studies have shown that the overexpression of SKP2 in several cancer types is correlated with poor clinical outcomes, underscoring its potential as a therapeutic target. Notably, emerging evidence has expanded the functional repertoire of SKP2 beyond cell cycle control to encompass metabolism, DNA repair, stemness, tumor microenvironment (TME) and immunotherapy response, positioning it as an increasingly attractive target for intervention. In this review, the oncogenic properties of SKP2 and its underlying mechanisms were elucidated in multiple cancer types. Moreover, we systematically summarized future directions for SKP2-targeted therapy.\u003Cbr>Keywords: SKP2, cancer, ubiquitination, degradation, drug resistance, treatment |\n| --- |\n| Introduction\u003Cbr>The UPS is a major intracellular protein degradation pathway. It covalently attaches ubiquitin molecules to target proteins for labeling and subsequent degradation. This process is sequentially regulated by E1 activating enzymes, E2 conjugating enzymes, and E3 ligases, which together control protein stability and activity in eukaryotic cells.1 Substrate selection matters due to the diversity of proteins within cells, as evidenced by the instrumental role of E3 ligases in this process. First, E3 ligases bind to specific substrates, ensuring precise ubiquitination. Second, E3 ligases recognize the ubiquitin on E2 ubiquitinconjugating enzymes and catalyze its covalent attachment to target proteins. Finally, E3 ligases can promote the elongation of ubiquitin chains or select different topological structures of ubiquitin linkage, thereby modulating the functional outcomes of ubiquitination.1 In addition, the type of ubiquitin chain formed can also affect the degradation pathway and efficiency of protein waste.2 Therefore, E3 ligases and ubiquitin chains are key components to the ubiquitination system.\u003Cbr>SKP2, as a member of E3 ligases, induces proteasome-mediated protein hydrolysis or regulates substrate function by binding K48-linked ubiquitin chains or K63-linked ubiquitin chains to its various substrates.3 Several studies have suggested that SKP2 can function as a cell cycle regulator that specifically recognizes phosphorylated cell cycle regulatory proteins and mediates their ubiquitination.4 Furthermor","cbCaigwtIfK2a1zk","https://ap.wps.com/l/cbCaigwtIfK2a1zk","pdf",12410584,24,"English","# Abstract\n# Introduction\n## Ubiquitin-proteasome system and E3 ligase regulation\n## SKP2 functions and clinical implications","[{\"question\":\"What role does the ubiquitin-proteasome system (UPS) play in cells, according to the review?\",\"answer\":\"The UPS regulates intracellular protein homeostasis by covalently labeling proteins with ubiquitin for subsequent degradation. This process depends on E1, E2, and E3 enzymes, which control protein stability and activity in eukaryotic cells.\"},{\"question\":\"How does SKP2 contribute to cancer progression?\",\"answer\":\"SKP2, as an E3 ubiquitin ligase, can induce proteasome-mediated degradation or modulate substrate functions by binding K48- or K63-linked ubiquitin chains to targets. Overexpression in multiple cancers is associated with poor clinical outcomes and chemoresistance acquisition.\"},{\"question\":\"What expanded functions of SKP2 are highlighted beyond cell cycle control?\",\"answer\":\"The review notes emerging evidence that SKP2 also impacts metabolism, DNA repair, stemness, the tumor microenvironment (TME), and immunotherapy response. These findings support SKP2 as an increasingly attractive therapeutic target.\"}]","SKP2 in Cancer: From Molecular Regulation to Therapeutic Vulnerabilities and Translational Perspectives | PDF",1790084101]