[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-345545-105":59,"doc-detail-345545-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","histone-deacetylase-enzyme-activity-is-not-the-universal-anticancer-target-of-hdac-inhibitors","Histone deacetylase enzyme activity is not the universal anticancer target of HDAC inhibitors","","Histone deacetylase inhibitors (HDIs) are used for hematologic cancers and are being tested widely, yet their mechanisms remain unclear. Unbiased bioinformatics analyses show that, for most cancer types, HDAC expression levels or genetic variants do not consistently link to carcinogenesis, patient survival, or cellular responses to HDIs. Whole-genome CRISPR screens fail to identify HDACs as genes controlling HDI responses. Experimental results further indicate that disrupting HDAC enzyme activity does not reproduce the anticancer and transcriptomic effects of specific HDIs, suggesting HDAC enzymatic activity is not always the functional target driving anti-cancer outcomes.",{"@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/histone-deacetylase-enzyme-activity-is-not-the-universal-anticancer-target-of-hdac-inhibitors/345545/",{"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/histone-deacetylase-enzyme-activity-is-not-the-universal-anticancer-target-of-hdac-inhibitors/345545.png","ImageObject",300,407,{"name":92,"@type":93},"Miles","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":14},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the central question about HDIs and HDACs addressed in the document?","Question",{"text":112,"@type":113},"Whether histone deacetylase (HDAC) enzyme activity is the universal functional target that drives the anticancer effects of HDAC inhibitors (HDIs).","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"What do the bioinformatics analyses suggest about HDACs across cancer types?",{"text":117,"@type":113},"For most cancers, HDAC expression levels or genetic variants do not consistently correlate with carcinogenesis, do not predict patient survival, and do not associate with cellular responses to HDIs.",{"name":119,"@type":110,"acceptedAnswer":120},"How do CRISPR library screens and follow-up experiments inform the proposed mechanism?",{"text":121,"@type":113},"Whole-genome CRISPR library screens do not identify HDACs as genes affecting cellular responses to HDIs, and manipulations that abolish HDAC-inhibiting activity can fail to eliminate HDI anticancer effects in vivo, indicating the target is not necessarily HDAC enzyme activity.","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},345545,1790182367,{"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":14,"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":145},13056703019404,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Signal Transduction [and Targeted Therapy](and Targeted Therapy www.nature.com/sigtrans)[ www.nature.com/sigtrans](and Targeted Therapy www.nature.com/sigtrans)  \nHistone deacetylase enzyme activity is not the universal anticancer target of HDAC inhibitors  \nChaitra Rai1, Hang Ruan 2, Xue Li3, Wenbo Li1, Hyun-Hwan Jeong4, Chengchuang Song 1, Panpan Liu1, Yingjie Chang3, Hao Fang3, Udhaya Kumar. S 1, Yuxiang Sun1, M. James You5, Dongyin Guan1, Zhandong Liu4, Leng Han 6 ✉, Xuben Hou 3 ✉ and Zheng Sun 1,7 ✉  \n|  |  |  |\n| --- | --- | --- |\n|  | Histone deacetylase inhibitors (HDIs) are approved for treating hematologic cancers and are currently being evaluated in hundreds of clinical trials for various cancers and other diseases, although their mechanisms of action remain poorly understood. Here, our unbiased bioinformatics analyses found that, for most cancer types, expression levels or genetic variants of histone deacetylase (HDACs) do not consistently correlate with carcinogenesis, do not predict cancer patient survival, and do not associate with cellular responses to HDIs. Whole-genome CRISPR library screens did not identify HDACs as genes affecting cellular responses to HDIs. Overexpression of dominant-negative Class I HDACs causes similar protein hyperacetylation as Class I-specific HDI FK228, but does not have similar cytotoxic or transcriptomic effects as FK228 in vitro, and does not alter the anticancer effects of FK228 in vivo in aliver cancer mouse model. Chemical manipulations of a pan-HDI SAHA can abolish its HDAC-inhibiting activity without altering its anticancer effects in vivo in an allograft colon cancer mouse model. These results suggest that HDAC enzyme activity is not necessarily the de facto target of HDIs for their anticancer effects. This finding encourages a shift away from a narrow focus on HDACs for understanding HDIs’ pharmacodynamics, opening new avenues for developing next-generation compounds for cancers |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n|  |  |  |\n| and beyond. |  |  |\n|  | Signal Transduction and Targeted Therapy (2026)11:218 ; [https://doi.org/10.1038/s41392-026-02698-1](https://doi.org/10.1038/s41392-026-02698-1) |  |\n|  |  |  |\n\nINTRODUCTION  \nHistone acetylation is believed to alter chromatin accessibility and regulate gene expression.1 Histone acetylation at lysine residues is controlled by the catalytic activity of histone acetyltransferases (HATs) and histone deacetylase (HDACs) .2 Mammalian HDACs are grouped into four classes based on sequence homology to their yeast counterparts: Class I Rpd3-like (HDAC1, HDAC2, HDAC3, and HDAC8); Class II Hda1-like (HDAC4, HDAC5, HDAC6, HDAC7, and HDAC9 as class IIa and HDAC10 as class IIb); Class III Sir2-like (SIRT1-7); and Class IV (HDAC11). Class I, II, and IV HDACs share a common zinc-dependent catalytic mechanism,3 whereas class III HDACs require NAD as the cofactor for their enzymatic activity. The Zn-dependent HDACs show conserved residues at their catalytic sites, including histidine, aspartate, and tyrosine.3 The tyrosine residue is significant for stabilizing the tetrahedral intermediate at the catalytic site and polarizing the substrate carbonyl for the nucleophilic attack.3 This key catalytic tyrosine residue is replaced by a histidine residue in class IIa HDACs, rendering them low catalytic activity.3,4 As a result, Class IIa HDACs enzyme activity is largely dependent on HDAC3, a Class I HDAC.5  \nHDIs inhibit HDAC enzymatic activity by chelating the catalytic zinc ion and blocking its access to substrates.6 The widely accepted pharmacological model posits that HDIs have three major structural units: a zinc-binding group (ZBG), a cap, and a linker in between.7 The cap is usually an aromatic, hydrophobic group that interacts with the enzyme’s surface. The ZBG can be a hydroxamic acid group or a benzamide group that chelates the zinc ion and directly inhibits the cat","cbCaigAFAQ0jlN2q","https://ap.wps.com/l/cbCaigAFAQ0jlN2q","pdf",7471136,17,"English","# Introduction\n## Histone acetylation and HDAC classes\n## HDI pharmacological model and zinc-dependent inhibition\n## Clinical use and approved HDIs","[{\"question\":\"What is the central question about HDIs and HDACs addressed in the document?\",\"answer\":\"Whether histone deacetylase (HDAC) enzyme activity is the universal functional target that drives the anticancer effects of HDAC inhibitors (HDIs).\"},{\"question\":\"What do the bioinformatics analyses suggest about HDACs across cancer types?\",\"answer\":\"For most cancers, HDAC expression levels or genetic variants do not consistently correlate with carcinogenesis, do not predict patient survival, and do not associate with cellular responses to HDIs.\"},{\"question\":\"How do CRISPR library screens and follow-up experiments inform the proposed mechanism?\",\"answer\":\"Whole-genome CRISPR library screens do not identify HDACs as genes affecting cellular responses to HDIs, and manipulations that abolish HDAC-inhibiting activity can fail to eliminate HDI anticancer effects in vivo, indicating the target is not necessarily HDAC enzyme activity.\"}]","Histone deacetylase enzyme activity is not the universal anticancer target of HDAC inhibitors | PDF",1790058045,43]