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A mechanistic study identifies the lysine methyltransferase SMYD2 as a clinically actionable master regulator of metastasis. SMYD2 overexpression does not drive primary tumor growth, but mammary-epithelium–specific SMYD2 loss increases survival by blocking metastasis. SMYD2 methylates BCAR3 at K334, enabling recognition by FMNL methyl-binding domains that remodel actin lamellipodia. Impaired BCAR3 methylation reduces migration and invasion in vitro and suppresses metastasis in vivo; SMYD2 inhibition blocks spread across models.",{"@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":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/cytoskeleton-remodeling-induced-by-smyd2-methyltransferase-drives-breast-cancer-metastasis/340880/",{"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/cytoskeleton-remodeling-induced-by-smyd2-methyltransferase-drives-breast-cancer-metastasis/340880.png","ImageObject",300,407,{"name":92,"@type":93},"Himbo","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does SMYD2 play in breast cancer metastasis?","Question",{"text":112,"@type":113},"SMYD2 is identified as a master regulator of breast cancer metastasis. It promotes metastatic ability without being required for primary tumor growth.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does SMYD2 mechanistically drive metastasis?",{"text":117,"@type":113},"SMYD2 methyltransferase methylates BCAR3 at lysine K334. The methylated BCAR3 is recognized by FMNL proteins, recruiting actin cytoskeleton regulators to cell edges and altering lamellipodia properties.",{"name":119,"@type":110,"acceptedAnswer":120},"What is the therapeutic implication of targeting the SMYD2 pathway?",{"text":121,"@type":113},"Genetic disruption of SMYD2 or impaired BCAR3 methylation reduces migration, invasiveness, and metastatic spread. Pharmacologic SMYD2 inhibition suppresses metastatic dissemination across multiple in vivo models, supporting a preventive therapeutic strategy targeting the SMYD2-BCAR3-FMNL axis.","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},340880,1790072055,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":44,"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},687197100911,"https://ap-avatar.wpscdn.com/avatar/a000239b6f1da00475?x-image-process=image/resize,m_fixed,w_180,h_180&k=1785132997149421697","Casanova et al. Cell Discovery (2024)10:12 [https://doi.org/10.1038/s41421-023-00644-x](https://doi.org/10.1038/s41421-023-00644-x)  \nCell Discovery  \n[www.nature.com/celldisc](www.nature.com/celldisc)  \nARTICLE Open Access  \nCytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis  \nAlexandre G. Casanova1, Gael S. Roth1,2, Simone Hausmann3, Xiaoyin Lu3, Ludivine J. M. Bischoff1,  \nEmilie M. Froeliger1, Lucid Belmudes4, Ekaterina Bourova-Flin1, Natasha M. Flores3, Ana Morales Benitez3, Tourkian Chasan3, Marcello Caporicci3, Jessica Vayr1, Sandrine Blanchet1, Francesco Ielasi1, Sophie Rousseaux1, Pierre Hainaut1, Or Gozani5, Muriel Le Romancer6, Yohann Couté4, Andres Palencia1, Pawel K. Mazur3 ✉ and Nicolas Reynoird1 ✉  \nAbstract  \nMalignant forms of breast cancer refractory to existing therapies remain a major unmet health issue, primarily due to metastatic spread. A better understanding of the mechanisms at play will provide better insights for alternative treatments to prevent breast cancer cell dispersion. Here, we identify the lysine methyltransferase SMYD2 as a clinically actionable master regulator of breast cancer metastasis. While SMYD2 is overexpressed in aggressive breast cancers, we notice that it is not required for primary tumor growth. However, mammary-epithelium specific SMYD2 ablation increases mouse overall survival by blocking the primary tumor cell ability to metastasize. Mechanistically, we identify BCAR3 as a genuine physiological substrate of SMYD2 in breast cancer cells. BCAR3 monomethylated at lysine K334 (K334me1) is recognized by a novel methyl-binding domain present in FMNLs proteins. These actin cytoskeleton regulators are recruited at the cell edges by the SMYD2 methylation signaling and modulate lamellipodia properties. Breast cancer cells with impaired BCAR3 methylation lose migration and invasiveness capacity in vitro and are ineffective in promoting metastases in vivo. Remarkably, SMYD2 pharmacologic inhibition efficiently impairs the metastatic spread of breast cancer cells, PDX and aggressive mammary tumors from genetically engineered mice. This study provides a rationale for innovative therapeutic prevention of malignant breast cancer metastatic progression by targeting the SMYD2-BCAR3-FMNL axis.  \nIntroduction  \nBreast cancer is the most common cancer in women and the second most common cancer overall. In particular, triple-negative breast cancer (TNBC, negative for estrogen receptor ER, progesterone receptor PR and human epidermal growth factor receptor 2 HER2) and basal-like breast cancer (mostly negative for ER, PR and HER2 with expression of basal markers), are the most aggressive subtypes of breast cancer. Both have limited therapeutic  \nCorrespondence: Pawel K. Mazur ([PKMazur@mdanderson.org](PKMazur@mdanderson.org)) or Nicolas Reynoird ([Nicolas.reynoird@univ-grenoble-alpes.fr](Nicolas.reynoird@univ-grenoble-alpes.fr))  \n1Grenoble Alpes University, CNRS UMR 5309, INSERM U 1209, Institute for Advanced Biosciences, Grenoble, France  \n2Clinique Universitaire d’ Hépato-gastroentérologie et Oncologie digestive, CHU Grenoble Alpes, Grenoble, France  \nFull list of author information is available at the end of the article  \noptions and high susceptibility to recurrence and metastases development1,2. Ultimately, a vast majority of breast cancer-related deaths are due to metastatic spread to distant organs, such as lungs and bones2,3. Therefore, it is important to provide alternative options preventing the development of metastases while treating primary tumors. In the course of a multi-step metastatic cascade, cancer cells acquire the ability to migrate and invade surrounding tissues4. The description of molecular mechanisms promoting invasive phenotype remain incomplete, and identifying critical molecular drivers is an urgent need to control malignant breast cancer progression5,6.  \nPosttranslational modifications (PTMs) of proteins, the major mechanism of prot","cbCaiqfH2nY0223J","https://ap.wps.com/l/cbCaiqfH2nY0223J","pdf",3580294,22,"English","# Abstract\n# Introduction","[{\"question\":\"What role does SMYD2 play in breast cancer metastasis?\",\"answer\":\"SMYD2 is identified as a master regulator of breast cancer metastasis. It promotes metastatic ability without being required for primary tumor growth.\"},{\"question\":\"How does SMYD2 mechanistically drive metastasis?\",\"answer\":\"SMYD2 methyltransferase methylates BCAR3 at lysine K334. The methylated BCAR3 is recognized by FMNL proteins, recruiting actin cytoskeleton regulators to cell edges and altering lamellipodia properties.\"},{\"question\":\"What is the therapeutic implication of targeting the SMYD2 pathway?\",\"answer\":\"Genetic disruption of SMYD2 or impaired BCAR3 methylation reduces migration, invasiveness, and metastatic spread. Pharmacologic SMYD2 inhibition suppresses metastatic dissemination across multiple in vivo models, supporting a preventive therapeutic strategy targeting the SMYD2-BCAR3-FMNL axis.\"}]","Cytoskeleton remodeling induced by SMYD2 methyltransferase drives breast cancer metastasis | PDF",1790039307,55]