[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-331791-105":59,"doc-detail-331791-en":130},{"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":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","targeting-the-phf8yy1-axis-suppresses-cancer-cell-growth-through-modulation-of-ros-research-article","Targeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS - Research Article","","High levels of mitochondrial reactive oxygen species (mROS) promote cancer development and are regulated by the electron transport chain (ETC). The study identifies an epigenetic control mechanism for ETC gene transcription, showing that PHF8 overexpression negatively correlates with ETC expression and acts as a co-repressor by demethylating the non-histone substrate YY1. Genetic or pharmacologic inhibition with iPHF8 suppresses YY1 methylation, ETC transcription, mROS production, and cancer cell growth, including in vivo 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/targeting-the-phf8yy1-axis-suppresses-cancer-cell-growth-through-modulation-of-ros-research-article/331791/",{"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/targeting-the-phf8yy1-axis-suppresses-cancer-cell-growth-through-modulation-of-ros-research-article/331791.png","ImageObject",300,407,{"name":92,"@type":93},"Jiven","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-14","2026-09-21",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 PHF8/YY1 axis play in regulating cancer cell growth?","Question",{"text":112,"@type":113},"PHF8 acts as a transcriptional co-repressor by demethylating the transcription factor YY1, enabling repression of ETC gene transcription that drives mROS production and cancer cell growth.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does iPHF8 affect mitochondrial ROS and ETC gene expression?",{"text":117,"@type":113},"iPHF8 targets PHF8 and inhibits mROS production by suppressing YY1 methylation and consequently reducing ETC gene transcription.",{"name":119,"@type":110,"acceptedAnswer":120},"Does targeting PHF8 show antitumor effects beyond cell culture?",{"text":121,"@type":113},"Yes. iPHF8 suppresses tumor growth in cell-line- and patient-derived xenografts in vivo, with evidence of potency and safety.","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},331791,1790182415,{"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":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":41,"preview_page_count":4},1099513958607,"https://ap-avatar.wpscdn.com/avatar/100002390cf8733938c?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778829742770036399","RESEARCH ARTICLE  \nCELL BIOLOGY  \n OPEN ACCESS  \nTargeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS  \nXiao-Nan Wua, b,1, Jia-yuan Lia, b,1, Qi Hea, b,1, Bo-qun Lib,1, Yao-hui Hea, b , Xu Panc, Ming-yue Wanga, b, Rui Sanga, b, Jian-cheng Dinga, b , Xiang Gaob , Zhen Wub,2, and Wen Liua, b,2  \nEdited by M. Celeste Simon, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; received November 23, 2022; accepted November 17, 2023  \nHigh levels of mitochondrial reactive oxygen species (mROS) are linked to cancer development, which is tightly controlled by the electron transport chain (ETC). However, the epigenetic mechanisms governing ETC gene transcription to drive mROS production and cancer cell growth remain to be fully characterized. Here, we report that protein demethylase PHF8 is overexpressed in many types of cancers, including colon and lung cancer, and is negatively correlated with ETC gene expression. While it is well known to demethylate histones to activate transcription, PHF8 demethylates transcription factorYY1, functioning as a co-repressor for a large set of nuclear-coded ETC genes to drive mROS production and cancer development. In addition to genetically ablating PHF8, pharmacologically targeting PHF8 with a specific chemical inhibitor, iPHF8, is potent in regulating YY1 methylation, ETC gene transcription, mROS production, and cell growth in colon and lung cancer cells. iPHF8 exhibits potency and safety in suppressing tumor growth in cell-line-and patient-derived xenografts in vivo. Our data uncover a key epigenetic mechanism underlying ETC gene transcriptional regulation, demonstrating that targeting the PHF8/YY1 axis has great potential to treat cancers.  \nReactive oxygen species (ROS) including superoxide (O2 − ), hydrogen peroxide (H2O2), hydroxyl radical (OH), and lipid hydroperoxide are oxygen (O2)-derived molecules. Increased levels of ROS are frequently observed in cancers, which are regarded to be a hallmark of cancer and associated with cancer development (1–3) .  \nMitochondria contribute the most to cellular ROS (4). During mitochondrial respiration, the electron transport chain (ETC), which consists of multiple complexes at the inner mitochondrial membrane, transfers electrons from the tricarboxylic (TCA) cycle to O2, the terminal electron acceptor (5, 6). The electrons that leak from the ETC react with O2 to produce O2 − (4). Dysregulation of the ETC leads to increased mROS (mitochondrial ROS) production (7, 8) . Transcription factors including NRF1/2, ERRα, and PGC1 a have been reported to participate in the transcriptional regulation of ETC genes (9) . However, the molecular mechanisms through which cancer cells reprogram ETC gene transcription to drive mROS production remain to be fully characterized.  \nPHF8, a plant homeodomain finger– and Jumonji C (JmjC) domain–containing protein, was found to be mutated in patients with X-linked mental retardation (XLMR) and cleft lip/palate (10–12) . PHF8 overexpression has been documented in various cancer types, highlighting the oncogenic role of PHF8 . PHF8 is known as a histone lysine demethylase that removes repressive histone marks H3K9me1/2, H3K27me2, and H4K20me1 (13–18). Functional studies on PHF8 in both physiological and pathological contexts have predominantly focused on its role as a transcriptional co-activator. The regulatory function of PHF8 is largely dependent on its enzymatic activity.  \nIn the current study, we report that PHF8 can function as a transcriptional co-repressor to regulate a large subset of ETC genes by directly demethylating a non histone substrate YY1, which drives mROS production and cancer cell growth. A small-molecule inhibitor, iPHF8, targeting the catalytic core of PHF8 is identified and demonstrated to inhibit mROS production, cell growth, and tumorigenesis in multiple types of cancer cells.  \nResults  \nPHF8 Interacts with YY1. We previously reported that PHF8, in co","cbCaifq3ijDKQ0Nu","https://ap.wps.com/l/cbCaifq3ijDKQ0Nu","pdf",1620457,12,"English","# Results\n## PHF8 interacts with YY1","[{\"question\":\"What role does the PHF8/YY1 axis play in regulating cancer cell growth?\",\"answer\":\"PHF8 acts as a transcriptional co-repressor by demethylating the transcription factor YY1, enabling repression of ETC gene transcription that drives mROS production and cancer cell growth.\"},{\"question\":\"How does iPHF8 affect mitochondrial ROS and ETC gene expression?\",\"answer\":\"iPHF8 targets PHF8 and inhibits mROS production by suppressing YY1 methylation and consequently reducing ETC gene transcription.\"},{\"question\":\"Does targeting PHF8 show antitumor effects beyond cell culture?\",\"answer\":\"Yes. iPHF8 suppresses tumor growth in cell-line- and patient-derived xenografts in vivo, with evidence of potency and safety.\"}]","Targeting the PHF8/YY1 axis suppresses cancer cell growth through modulation of ROS - Research Article | PDF",1789995175]