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Genetic abrogation of NMT1 via CRISPR/Cas9 unexpectedly reduces mitochondrial respiratory complex I proteins, with first-in-class NMTI PCLX-001 (zelenirstat) reproducing the effect. The main downregulated myristoylated factor, NDUFAF4, drives loss of complex I, oxidative phosphorylation, respiration, and metabolome disruption. Targeting oxidative phosphorylation alongside signaling helps explain zelenirstat lethality, supporting further clinical development.",{"@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":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/multiomics-analysis-identifies-oxidative-phosphorylation-as-a-cancer-vulnerability-arising-from-myristoylation-inhibition/330583/",{"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/multiomics-analysis-identifies-oxidative-phosphorylation-as-a-cancer-vulnerability-arising-from-myristoylation-inhibition/330583.png","ImageObject",300,407,{"name":92,"@type":93},"Aurora","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-07","2026-09-21",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 role do NMT1 and NMT2 play in the study’s cancer context?","Question",{"text":113,"@type":114},"NMT1 and NMT2 catalyze myristate transfer to proteins, enabling membrane targeting and signaling. The study reports dysregulated NMT2 levels via epigenetic suppression, especially in hematologic malignancies.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How is cancer sensitivity to NMT inhibitors characterized in the study?",{"text":118,"@type":114},"Sensitivity is associated with NMT2 loss and NMT1 dependency and correlates with a 54-gene myristoylation inhibition sensitivity signature (MISS-54) enriched in multiple cancer types.",{"name":120,"@type":111,"acceptedAnswer":121},"Why does inhibiting NMT1 lead to mitochondrial dysfunction rather than primarily signaling changes?",{"text":122,"@type":114},"Differential proteomics shows that abrogating NMT1 mainly reduces mitochondrial respiratory complex I proteins. The most downregulated myristoylated mitochondrial protein is NDUFAF4, and its loss leads to complex I loss, oxidative phosphorylation, respiration, and metabolome changes.","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},330583,1790019590,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":39,"category_name":40,"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},4810365810221,"https://ap-avatar.wpscdn.com/davatar_155a257f0dc6eb9ab79c44ca47cae57d","Beauchamp et al.  \nJournal of Translational Medicine (2024) 22:431 [https://doi.org/10.1186/s12967-024-05150-6](https://doi.org/10.1186/s12967-024-05150-6)  \nJournal of Translational Medicine  \n RESEARCH Open Access  \nMultiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition  \nErwan Beauchamp1, Jay M. Gamma2, Christopher R. Cromwell3, Eman W. Moussa4, Rony Pain5, Morris A. Kostiuk5, Claudia Acevedo‑Morantes5, Aishwarya Iyer5, Megan Yap5, Krista M. Vincent6, Lynne M. Postovit6, Olivier Julien4, Basil P. Hubbard3, John R. Mackey 1 and Luc G. Berthiaume 1,5*  \nAbstract  \nBackground In humans, two ubiquitously expressed N‑myristoyltransferases, NMT1 and NMT2, catalyze myristate transfer to proteins to facilitate membrane targeting and signaling. We investigated the expression of NMTs in numer‑ ous cancers and found that NMT2 levels are dysregulated by epigenetic suppression, particularly so in hematologic malignancies. This suggests that pharmacological inhibition of the remaining NMT1 could allow for the selective kill‑ ing of these cells, sparing normal cells with both NMTs.  \nMethods and results Transcriptomic analysis of 1200 NMT inhibitor (NMTI)‑treated cancer cell lines revealed  \nthat NMTI sensitivity relates not only to NMT2 loss or NMT1 dependency, but also correlates with a myristoylation inhibition sensitivity signature comprising 54 genes (MISS‑54) enriched in hematologic cancers as well as testis, brain, lung, ovary, and colon cancers. Because non‑myristoylated proteins are degraded by a glycine‑specific N‑degron, differential proteomics revealed the major impact of abrogating NMT1 genetically using CRISPR/Cas9 in cancer cells was surprisingly to reduce mitochondrial respiratory complex I proteins rather than cell signaling proteins, some of which were also reduced, albeit to a lesser extent. Cancer cell treatments with the first‑in‑class NMTI PCLX‑001 (zelenirstat), which is undergoing human phase 1/2a trials in advanced lymphoma and solid tumors, recapitulated these effects. The most downregulated myristoylated mitochondrial protein was NDUFAF4, a complex I assembly factor. Knockout of NDUFAF4 or in vitro cell treatment with zelenirstat resulted in loss of complex I, oxidative phospho‑ rylation and respiration, which impacted metabolomes.  \nConclusions Targeting of both, oxidative phosphorylation and cell signaling partly explains the lethal effects of zele‑ nirstat in select cancer types. While the prognostic value of the sensitivity score MISS‑54 remains to be validated in patients, our findings continue to warrant the clinical development of zelenirstat as cancer treatment.  \nKeywords N‑myristoylation, N‑myristoyltransferase, NMT inhibitor (NMTI), PCLX‑001 (zelenirstat), Cancer, Complex I, NDUFAF4, Oxidative phosphorylation, Respiration  \n*Correspondence:  \nLuc G. Berthiaume  \n[luc.berthiaume@ualberta.ca](luc.berthiaume@ualberta.ca)  \nFull list of author information is available at the end of the article  \n© The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedicati","cbCaifdCRWIG0M8u","https://ap.wps.com/l/cbCaifdCRWIG0M8u","pdf",6319439,28,"English","# Abstract\n## Background\n## Methods and results\n## Conclusions\n# Introduction\n## N-myristoylation is essential for protein function in cancer\n## NMT inhibitors and limitations of earlier tools","[{\"question\":\"What role do NMT1 and NMT2 play in the study’s cancer context?\",\"answer\":\"NMT1 and NMT2 catalyze myristate transfer to proteins, enabling membrane targeting and signaling. The study reports dysregulated NMT2 levels via epigenetic suppression, especially in hematologic malignancies.\"},{\"question\":\"How is cancer sensitivity to NMT inhibitors characterized in the study?\",\"answer\":\"Sensitivity is associated with NMT2 loss and NMT1 dependency and correlates with a 54-gene myristoylation inhibition sensitivity signature (MISS-54) enriched in multiple cancer types.\"},{\"question\":\"Why does inhibiting NMT1 lead to mitochondrial dysfunction rather than primarily signaling changes?\",\"answer\":\"Differential proteomics shows that abrogating NMT1 mainly reduces mitochondrial respiratory complex I proteins. The most downregulated myristoylated mitochondrial protein is NDUFAF4, and its loss leads to complex I loss, oxidative phosphorylation, respiration, and metabolome changes.\"}]","Multiomics analysis identifies oxidative phosphorylation as a cancer vulnerability arising from myristoylation inhibition | PDF",1789989461,71]