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Emerging research emphasizes reversible epigenetic alterations—DNA methylation, histone modifications, chromatin remodeling dysregulation, and non-coding RNA networks—that govern each phase of skeletal colonization. Mechanistic pathways include tumor-suppressor promoter hypermethylation, global DNA hypomethylation, histone modifier control of osteoclast signaling and dormancy, and SWI/SNF-driven enhancer–promoter reprogramming. Exosome-mediated non-coding RNAs modulate RANKL/OPG and pre-metastatic niche formation. These insights accelerate epigenetic therapy development, including DNMT, HDAC, EZH2, BET, and KDM1A inhibitors, plus CRISPR/dCas9 epigenome editing and RNA-targeted approaches, aiming at precision oncology.",{"@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/epigenetic-modulation-and-bone-metastasis-evolving-therapeutic-strategies/374745/",{"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/epigenetic-modulation-and-bone-metastasis-evolving-therapeutic-strategies/374745.png","ImageObject",300,407,{"name":92,"@type":93},"Dipper","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-26","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What epigenetic mechanisms drive bone metastasis progression?","Question",{"text":113,"@type":114},"The review highlights reversible epigenetic changes such as DNA methylation, histone modifications, chromatin remodeling dysregulation, and non-coding RNA networks that regulate skeletal colonization, dormancy, and reactivation.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How do histone modifiers and chromatin remodelers influence metastatic behavior in bone?",{"text":118,"@type":114},"Key histone modifiers (e.g., KLF5, EZH2, KDM4/6) regulate osteoclastogenic signaling and the switch between metastatic dormancy and reactivation. SWI/SNF remodelers like BRG1/BRM reconfigure enhancer–promoter interactions to promote bone tropism.",{"name":120,"@type":111,"acceptedAnswer":121},"What therapeutic strategies are discussed for epigenetic modulation in bone metastasis?",{"text":122,"@type":114},"The review covers DNMT inhibitors, HDAC inhibitors, and agents targeting EZH2, BET proteins, and KDM1A, including combination approaches with bisphosphonates or immune checkpoint inhibitors, as well as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies.","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},374745,1790241360,{"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},1374404997633,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Review  \nEpigenetic Modulation and Bone Metastasis: Evolving Therapeutic Strategies  \nMahmoud Zhra 1, Jasmine Hanafy Holail 2 and Khalid S. Mohammad 1, *  \nAcademic Editor: Chen Ling  \nReceived: 27 May 2025  \nRevised: 25 July 2025  \nAccepted: 28 July 2025  \nPublished: 31 July 2025  \nCitation: Zhra, M.; Holail, J.H.; Mohammad, K.S. Epigenetic Modulation and Bone Metastasis:  \nEvolving Therapeutic Strategies. Pharmaceuticals 2025, 18, 1140 . [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ph18081140  \nCopyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://creativecommons.org/](https://creativecommons.org/)[ ](https://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/)) .  \n1 Department of Anatomy and Genetics, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; [mzahra@alfaisal.edu](mzahra@alfaisal.edu)  \n2 Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia; [jholail@alfaisal.edu](jholail@alfaisal.edu)  \n* Correspondence: [kmohammad@alfaisal.edu](kmohammad@alfaisal.edu)  \nAbstract  \nBone metastasis remains a significant cause of morbidity and diminished quality of life inpatients with advanced breast, prostate, and lung cancers. Emerging research highlights the pivotal role of reversible epigenetic alterations, including DNA methylation, histone modifications, chromatin remodeling complex dysregulation, and non-coding RNA networks, in orchestrating each phase of skeletal colonization. Site-specific promoter hypermethylation of tumor suppressor genes such as HIN-1 andRASSF1A, alongside global DNA hypomethylation that activates metastasis-associated genes, contributes to cancer cell plasticity and facilitates epithelial-to-mesenchymal transition (EMT). Key histone modifiers, including KLF5, EZH2, and the demethylases KDM4/6, regulate osteoclastogenic signaling pathways and the transition between metastatic dormancy and reactivation. Simultaneously, SWI/SNF chromatin remodelers such as BRG1 and BRM reconfigure enhancer–promoter interactions that promote bone tropism. Non-coding RNAs, including miRNAs, lncRNAs, and circRNAs (e.g., miR-34a, NORAD, circIKBKB), circulate via exosomes to modulate the RANKL/OPG axis, thereby conditioning the bone microenvironment and fostering the formation of a pre-metastatic niche. These mechanistic insights have accelerated the development of epigenetic therapies. DNA methyltransferase inhibitors (e.g., decitabine, guadecitabine) have shown promise in attenuating osteoclast differentiation, while histone deacetylase inhibitors display context-dependent effects on tumor progression and bone remodeling. Inhibitors targeting EZH2, BET proteins, and KDM1A are now advancing through early-phase clinical trials, often in combination with bisphosphonates or immune checkpoint inhibitors. Moreover, novel approaches such as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies offer locus-specific reprogramming potential. Together, these advances position epigenetic modulation as a promising axis in precision oncology aimed at interrupting the pathological crosstalk between tumor cells and the bone microenvironment. This review synthesizes current mechanistic understanding, evaluates the therapeutic landscape, and outlines the translational challenges ahead in leveraging epigenetic science to prevent and treat bone metastases.  \nKeywords: bone metastasis; epigenetic therapy; DNA methylation; histone modification; non-coding RNAs; tumor microenvironment; bone-targeting agents  \n1. Introduction  \nBone metastasis is a prevalent and serious complication of advanced cancers, notably breast, prostate, and lung cancers. It occurs when cancer cells disseminate from their pri-  \nmary sites to the bone, leading to skeletal-related ev","cbCait3Hnu2KVHo9","https://ap.wps.com/l/cbCait3Hnu2KVHo9","pdf",2210223,38,"English","# Abstract\n## Keywords\n# Introduction\n## Bone microenvironment and the metastatic niche\n## Osteoclast/osteoblast contributions and lesion types","[{\"question\":\"What epigenetic mechanisms drive bone metastasis progression?\",\"answer\":\"The review highlights reversible epigenetic changes such as DNA methylation, histone modifications, chromatin remodeling dysregulation, and non-coding RNA networks that regulate skeletal colonization, dormancy, and reactivation.\"},{\"question\":\"How do histone modifiers and chromatin remodelers influence metastatic behavior in bone?\",\"answer\":\"Key histone modifiers (e.g., KLF5, EZH2, KDM4/6) regulate osteoclastogenic signaling and the switch between metastatic dormancy and reactivation. SWI/SNF remodelers like BRG1/BRM reconfigure enhancer–promoter interactions to promote bone tropism.\"},{\"question\":\"What therapeutic strategies are discussed for epigenetic modulation in bone metastasis?\",\"answer\":\"The review covers DNMT inhibitors, HDAC inhibitors, and agents targeting EZH2, BET proteins, and KDM1A, including combination approaches with bisphosphonates or immune checkpoint inhibitors, as well as CRISPR/dCas9-based epigenome editing and RNA-targeted therapies.\"}]","Epigenetic Modulation and Bone Metastasis: Evolving Therapeutic Strategies | PDF",1790202307,96]