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This study shows HLTF is significantly reduced in hepatocellular carcinoma (HCC) tissues and correlates with patient survival. Mechanistically, elevated β-TrCP–mediated ubiquitination and degradation suppress HLTF, while HLTF knockdown enhances p62 transcriptional activity and mTOR activation, driving HCC growth and metastasis. Targeting the mTOR axis blocks β-TrCP–driven and HLTF-silencing–mediated tumorigenesis.",{"@graph":69,"@context":123},[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/degradation-of-helicase-like-transcription-factor-hltf-by-trcp-promotes-hepatocarcinogenesis-via-activation-of-the-p62mtor-axis/406055/",{"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/degradation-of-helicase-like-transcription-factor-hltf-by-trcp-promotes-hepatocarcinogenesis-via-activation-of-the-p62mtor-axis/406055.png","ImageObject",300,407,{"name":92,"@type":93},"Chumphorn","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-05","2026-09-28",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What role does HLTF play according to the article?","Question",{"text":113,"@type":114},"HLTF is described as contributing to genome stability and tumor suppression, and its downregulation is linked to HCC progression.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does β-TrCP affect HLTF and HCC progression?",{"text":118,"@type":114},"β-TrCP increases ubiquitination and degradation of HLTF, and this contributes to p62-dependent transcriptional activity and mTOR activation that promote hepatocarcinogenesis.",{"name":120,"@type":111,"acceptedAnswer":121},"Why is the p62/mTOR axis important in this study?",{"text":122,"@type":114},"The study indicates that HLTF knockdown enhances p62 activity and activates mTOR, and that mTOR inhibition effectively blocks tumorigenesis and metastasis driven by β-TrCP overexpression or HLTF knockdown.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},406055,1790912707,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146,"preview_page_count":4},2336475401981,"https://ap-avatar.wpscdn.com/avatar/22000c94efd8d5204d?x-image-process=image/resize,m_fixed,w_180,h_180&k=1786935347598174694","Journal of Molecular Cell Biology (2023), 15(2), mjad012 [https://doi.org/10.1093/jmcb/mjad012](https://doi.org/10.1093/jmcb/mjad012)  \nPublished online February 23, 2023  \nArticle  \nDegradation of helicase-like transcription factor (HLTF) by β-TrCP promotes hepatocarcinogenesis via activation of the p62/mTOR axis  \nYe Tan1 , 2 ,†, Di Wu1 ,†, Ze-Yu Liu1 ,†, Hong-Qiang Yu1 ,†, Xiang-Ru Zheng2 ,†, Xiao-Tong Lin1 , Ping Bie2 , Lei-Da Zhang1 , and Chuan-Ming Xie 1 , *  \n1 Key Laboratory of Hepatobiliary and Pancreatic Surgery, Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China  \n2 Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Chongqing Medical University (Gener Hospital), Chongqing 401120, China  \n† These authors contributed equally to this work.  \n* Correspondence to: Chuan-Ming Xie, E-mail: [cmxie@tmmu.edu.cn](cmxie@tmmu.edu.cn), [chuanming506@126.com](chuanming506@126.com)  \nEdited by Hua Lu  \nHelicase-like transcription factor (HLTF) has been found to be involved in the maintenance of genome stability and tumour suppression, but whether its downregulation in cancers is associated with posttranslational regulation remains unclear. Here, we observed that HLTF was significantly downregulated in hepatocellular carcinoma (HCC) tissues and positively associated with the survival of HCC patients. Mechanistically, the decreased expression of HLTF in HCC was attributed to elevated β-TrCP-mediated ubiquitination and degradation. Knockdown of HLTF enhanced p62 transcriptional activity and mammalian target of rapamycin (mTOR) activation, leading to HCC tumourigenesis. Inhibition of mTOR effectively blocked β-TrCP overexpression- or HLTF knockdownmediated HCC tumourigenesis and metastasis. Furthermore, in clinical tissues, decreased HLTF expression was positively correlated with elevated expression of β-TrCP, p62, or p-mTOR in HCC patients. Overall, our data not only uncover new roles of HLTF in HCC cell proliferation and metastasis, but also reveal a novel posttranslational modification of HLTF by β-TrCP, indicating that the β-TrCP/HLTF/p62/mTOR axis may be a new oncogenic driver involved in HCC development. This finding provides a potential therapeutic strategy for HCC patients by targeting the β-TrCP/HLTF/p62/mTOR axis.  \nKeywords: HLTF, β-TrCP, mTOR, ubiquitination, hepatocellular carcinoma, cell proliferation, metastasis  \nIntroduction  \nHepatocellular carcinoma (HCC) remains one of the leading causes of cancer death, ranking third in global cancer-related mortality (Sung et al., 2021) . Surprising advances in treatment have been achieved in the past decade; for example, the combination of immune-checkpoint inhibitors with angiogenesis inhibitors improved survival outcomes compared with sorafenib alone in unresectable HCC patients (Finn et al., 2020) . However, the general prognosis remains dismal. With the develop-  \nReceived June 28, 2022 . Revised November 27, 2022. Accepted February 22, 2023 .© The Author(s) (2023) . Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, CEMCS, CAS.  \nThis is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License ([http://creativecommons.org/licenses/](http://creativecommons.org/licenses/)[ ](http://creativecommons.org/licenses/)[by-nc/4.0/](by-nc/4.0/)), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use,  \nplease contact [journals.permissions@oup.com](journals.permissions@oup.com)  \nment of next-generation sequencing, driving mutations in TP53, CTNNB1, ARID1A, etc. have been identified in HCC. However, unlike the critical mutation of EGFR in non-small cell lung cancer, which is targetable, the majority ofthose in HCC are undruggable at present. As the absence of specific treatment targeting genes","cbCaijqQo6MpGORV","https://ap.wps.com/l/cbCaijqQo6MpGORV","pdf",2507481,14,"English","# Introduction\n## Research background and clinical context\n## Chromatin regulation and SWI/SNF complexes\n## HLTF as an SWI/SNF-related factor","[{\"question\":\"What role does HLTF play according to the article?\",\"answer\":\"HLTF is described as contributing to genome stability and tumor suppression, and its downregulation is linked to HCC progression.\"},{\"question\":\"How does β-TrCP affect HLTF and HCC progression?\",\"answer\":\"β-TrCP increases ubiquitination and degradation of HLTF, and this contributes to p62-dependent transcriptional activity and mTOR activation that promote hepatocarcinogenesis.\"},{\"question\":\"Why is the p62/mTOR axis important in this study?\",\"answer\":\"The study indicates that HLTF knockdown enhances p62 activity and activates mTOR, and that mTOR inhibition effectively blocks tumorigenesis and metastasis driven by β-TrCP overexpression or HLTF knockdown.\"}]","Degradation of helicase-like transcription factor (HLTF) by β-TrCP promotes hepatocarcinogenesis via activation of the p62/mTOR axis | PDF",1790563327,35]