[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-373443-105":3,"doc-detail-373443-en":81,"detail-sidebar-cat-0-en-105":99},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","wwp1-mediates-the-ubiquitination-and-degradation-of-hipk3-in-bladder-cancer-cells","WWP1 mediates the ubiquitination and degradation of HIPK3 in bladder cancer cells","","Protein homeostasis is regulated largely by posttranslational modifications, yet how these controls shape HIPK3 function in bladder cancer is insufficiently understood. This study identifies WWP1 as an E3 ubiquitin ligase that targets HIPK3, reducing HIPK3 protein abundance by promoting ubiquitination. WWP1 directly binds HIPK3 and induces K48-linked polyubiquitination at K1187, forming a WWP1/HIPK3 axis that influences chemosensitivity via JNK signaling. Myc enhances WWP1 expression, linking transcriptional control to PTM-mediated HIPK3 regulation.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/wwp1-mediates-the-ubiquitination-and-degradation-of-hipk3-in-bladder-cancer-cells/373443/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/wwp1-mediates-the-ubiquitination-and-degradation-of-hipk3-in-bladder-cancer-cells/373443.png","ImageObject",300,407,{"name":42,"@type":43},"Fahsai","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-27","2026-09-23",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What role does WWP1 play in HIPK3 regulation?","Question",{"text":63,"@type":64},"WWP1 functions as an E3 ubiquitin ligase that targets HIPK3, facilitating its ubiquitination and subsequent degradation, which lowers HIPK3 protein levels.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does WWP1 modify HIPK3 to promote degradation?",{"text":68,"@type":64},"WWP1 directly interacts with HIPK3 and promotes K48-linked polyubiquitination at the K1187 site, marking HIPK3 for degradation.",{"name":70,"@type":61,"acceptedAnswer":71},"How is chemosensitivity connected to the WWP1/HIPK3 axis?",{"text":72,"@type":64},"The WWP1/HIPK3 axis modulates cancer cell chemosensitivity by regulating the JNK signaling pathway.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},373443,1790305203,{"code":4,"msg":82,"data":83},"success",{"doc_id":79,"user_id":84,"nickname":42,"user_avatar":85,"doc_module":4,"category_id":86,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":87,"file_id":88,"file_url":89,"file_type":90,"file_size":91,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":92,"language":93,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":94,"faqs":95,"seo_title":96,"seo_description":12,"update_tm":97,"read_time":98},549768702563,"https://ap-avatar.wpscdn.com/avatar/8000c4aa63b76e948b?x-image-process=image/resize,m_fixed,w_180,h_180&k=1786536092046926083",7,"RESEARCH ARTICLE  \nWWP1 mediates the ubiquitination and degradation of HIPK3 in bladder cancer cells  \nReceived for publication, September 8, 2024, and in revised form, March 20, 2025 Published, Papers in Press, April 23, 2025, [https://doi.org/10.1016/j.jbc.2025.108528](https://doi.org/10.1016/j.jbc.2025.108528)  \nHaichao Chen 1, Xinyu Na2, Pengcheng Hu3, Qi Ma 1, and Rui Yu3, *  \nFrom the 1Department of Urology, The First Affiliated Hospital of Ningbo University, Ningbo, Zhejiang Province, China; 2Department of Urology, Zhenhai People’s Hospital, Ningbo, Zhejiang Province, China; 3Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Health Science Center, Ningbo University, Ningbo, Zhejiang Province, China  \nReviewed by members of the JBC Editorial Board. Edited by George DeMartino  \nProtein homeostasis is primarily regulated by posttranslational modifications (PTMs). HIPK3 has been recognized as a tumor suppressor across various cancers. However, the impact of PTMs on HIPK3 remains insufficiently explored. This study identified WWP1 as an E3 ubiquitin ligase targeting HIPK3, demonstrating that WWP1 downregulates HIPK3 protein levels by facilitating its ubiquitination. Mechanistically, WWP1 directly interacts with HIPK3, promoting K48-linked polyubiquitination at the K1187 site. The WWP1/HIPK3 axis modulates cancer cell chemosensitivity through the regulation of the JNK signaling pathway. Additionally, Myc was found to act as a transcription factor, enhancing WWP1 expression. These findings offer novel insights into the regulation of HIPK3 at the PTM level.  \nBladder cancer (BCa), an aggressive tumor of the genitourinary system, ranks as the 10th most commonly diagnosed cancer worldwide (1). Several factors, including smoking, alcohol consumption, and obesity, contribute to the progression of BCa (2). Despite advancements in surgical and adjuvant treatments, the prognosis for patients with BCa remains poor (3). Therefore, understanding the underlying mechanisms of BCa tumorigenesis and developing potential treatment strategies is essential.  \nThe homeodomain-interacting protein kinase (HIPK) family comprises four evolutionarily conserved serine/threonine kinases: HIPK1-4 (4). HIPK1-3 are structurally related, containing an N-terminal kinase region and multiple other domains that facilitate protein interactions (5). For instance, HIPK3 interacts with FADD, mediating its phosphorylation and inhibiting Fas-induced JNK signaling activation (6). Increasing evidence suggests that HIPK3 acts as a tumor suppressor in various cancers. For example, reduced HIPK3 expression correlates with poor survival in patients with clear cell renal cell carcinoma (7). Additionally, low HIPK3 levels contribute to cisplatin resistance in gastric cancer, with overexpression of HIPK3 overcoming this resistance (8). Furthermore, HIPK3 downregulation is significantly associated with poor prognosis in other cancers (9).  \n* For correspondence: Rui Yu, [yurui@nbu.edu.cn](yurui@nbu.edu.cn).  \nHowever, the mechanisms regulating HIPK3 protein levels remain unclear.  \nIn eukaryotic cells, protein homeostasis is regulated by a complex protein degradation network. Two canonical systems involved in protein degradation are the autophagylysosome system and the ubiquitin-proteasome system (10). Ubiquitination, a common post-translational modification (PTM), tags target proteins with ubiquitin, leading to their degradation by the 26S proteasome complex (11). Ubiquitination is tightly regulated by three core enzymes: the ubiquitin-activating enzyme (E1), ubiquitin-conjugating enzyme (E2), and ubiquitin-protein ligase (E3) (11). E3 ligases recognize specific substrates and mediate the transfer of ubiquitin to lysine residues on target proteins. To date, over 600 E3 ligases have been identified in humans, categorized into three groups based on their ubiquitination domains: RBR (RING-Between-RING), RING (Really Interesting New Gene), and HECT (Homo","cbCaisNkmX7hRXVF","https://ap.wps.com/l/cbCaisNkmX7hRXVF","pdf",4354505,15,"English","# Results\n## WWP1 interacts with HIPK3\n## WWP1 promotes the degradation of HIPK3","[{\"question\":\"What role does WWP1 play in HIPK3 regulation?\",\"answer\":\"WWP1 functions as an E3 ubiquitin ligase that targets HIPK3, facilitating its ubiquitination and subsequent degradation, which lowers HIPK3 protein levels.\"},{\"question\":\"How does WWP1 modify HIPK3 to promote degradation?\",\"answer\":\"WWP1 directly interacts with HIPK3 and promotes K48-linked polyubiquitination at the K1187 site, marking HIPK3 for degradation.\"},{\"question\":\"How is chemosensitivity connected to the WWP1/HIPK3 axis?\",\"answer\":\"The WWP1/HIPK3 axis modulates cancer cell chemosensitivity by regulating the JNK signaling pathway.\"}]","WWP1 mediates the ubiquitination and degradation of HIPK3 in bladder cancer cells | PDF",1790199587,38,{"code":4,"msg":82,"data":100},[101,105,109,113,118,123,126,130,135,138,142],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":102,"show_sort_weight":103,"slug":104},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":106,"show_sort_weight":107,"slug":108},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":110,"show_sort_weight":111,"slug":112},"Exam",70,"exam",{"id":114,"doc_module":4,"doc_module_name":25,"category_name":115,"show_sort_weight":116,"slug":117},5,"Comic",60,"comic",{"id":119,"doc_module":4,"doc_module_name":25,"category_name":120,"show_sort_weight":121,"slug":122},6,"Technology",50,"technology",{"id":86,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":124,"slug":125},40,"healthcare",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":127,"show_sort_weight":128,"slug":129},"Research & Report",30,"research-report",{"id":131,"doc_module":4,"doc_module_name":25,"category_name":132,"show_sort_weight":133,"slug":134},9,"Religion & Spirituality",20,"religion-spirituality",{"id":133,"doc_module":4,"doc_module_name":25,"category_name":136,"show_sort_weight":133,"slug":137},"World Cup","world-cup",{"id":139,"doc_module":4,"doc_module_name":25,"category_name":140,"show_sort_weight":139,"slug":141},10,"Lifestyle","lifestyle",{"id":143,"doc_module":4,"doc_module_name":25,"category_name":144,"show_sort_weight":114,"slug":145},19,"General","general"]