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Abnormal lipid metabolism, especially increased cholesterol biosynthesis, supports malignant progression, yet the drivers of this dysregulation remain unclear. The study identifies PKMYT1 as a key kinase controlling cholesterol synthesis in TNBC and shows its elevated expression predicts unfavorable prognosis. Mechanistically, PKMYT1 activates the TNF/TRAF1/AKT axis to enhance SREBP2-mediated cholesterol biosynthetic enzymes.",{"@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/pkmyt1-knockdown-inhibits-cholesterol-biosynthesis-and-promotes-the-drug-sensitivity-of-triple-negative-breast-cancer-cells-to-atorvastatin/330967/",{"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/pkmyt1-knockdown-inhibits-cholesterol-biosynthesis-and-promotes-the-drug-sensitivity-of-triple-negative-breast-cancer-cells-to-atorvastatin/330967.png","ImageObject",300,407,{"name":92,"@type":93},"Noah","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-03","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",12,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"What is the main finding about PKMYT1 in triple-negative breast cancer (TNBC)?","Question",{"text":113,"@type":114},"PKMYT1 is identified as a key driver of cholesterol biosynthesis in TNBC cells, and its aberrant overexpression correlates with unfavorable prognostic outcomes.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"How does PKMYT1 promote cholesterol biosynthesis mechanistically?",{"text":118,"@type":114},"PKMYT1 enhances SREBP2-mediated expression of cholesterol biosynthesis enzymes by activating the TNF/TRAF1/AKT signaling pathway.",{"name":120,"@type":111,"acceptedAnswer":121},"What is the effect of PKMYT1 knockdown on statin-mediated cholesterol synthesis and atorvastatin sensitivity?",{"text":122,"@type":114},"Downregulating PKMYT1 significantly inhibits feedback upregulation of cholesterol biosynthesis induced by statins, while PKMYT1 knockdown increases the drug sensitivity of TNBC cells to atorvastatin.","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},330967,1790159012,{"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":36,"preview_page_count":4},8796095462418,"https://ap-avatar.wpscdn.com/avatar/80000253c1241d02b47?x-image-process=image/resize,m_fixed,w_180,h_180&k=1778826106357471780","Submitted 6 February 2024 Accepted 24 June 2024  \nPublished 12 July 2024  \nCorresponding author Shuqun Zhang, [shuqun_zhang1971@163.com](shuqun_zhang1971@163.com)  \nAcademic editor Jincheng Wang  \nAdditional Information and Declarations can be found on page 13  \nDOI 10.7717/peerj.17749  \n Copyright 2024 Gao et al.  \nDistributed under  \nCreative Commons CC-BY 4.0  \nPKMYT1 knockdown inhibits cholesterol biosynthesis and promotes the drug sensitivity of triple-negative breast cancer cells to atorvastatin  \nWei Gao 1, *, Xin Guo2, *, Linlin Sun3, Jinwei Gai3, Yinan Cao4 and Shuqun Zhang1  \n1 Department of Oncology, The Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China  \n2 Department of Breast Surgery, The First Affiliated Hospital of Dalian Medical University, Dalian, China  \n3 Day Surgery Center, Dalian Municipal Central Hospital, Dalian, China  \n4 Graduate School of Dalian Medical University, Dalian, China  \n* These authors contributed equally to this work.  \nABSTRACT  \nTriple negative breast cancer (TNBC) as the most aggressive molecular subtype of breast cancer is characterized by high cancer cell proliferation and poor patient prognosis. Abnormal lipid metabolism contributes to the malignant process of cancers. Study observed significantly enhanced cholesterol biosynthesis in TNBC. However, the mechanisms underlying the abnormal increase of cholesterol biosynthesis in TNBC are still unclear. Hence, we identified a member of the serine/ threonine protein kinase family PKMYT1 as a key driver of cholesterol synthesis in TNBC cells. Aberrantly high-expressed PKMYT1 in TNBC was indicative of unfavorable prognostic outcomes. In addition, PKMYT1 promoted sterol regulatory element-binding protein 2 (SREBP2)-mediated expression of enzymes related to cholesterol biosynthesis through activating the TNF/ TNF receptor-associated factor 1 (TRAF1)/AKT pathway. Notably, downregulation of PKMYT1 significantly inhibited the feedback upregulation of statin-mediated cholesterol biosynthesis, whereas knockdown of PKMYT1 promoted the drug sensitivity of atorvastatin in TNBC cells. Overall, our study revealed a novel function of PKMYT1 in TNBC cholesterol biosynthesis, providing a new target for targeting tumor metabolic reprogramming in the cancer.  \nSubjects Cell Biology, Molecular Biology, Oncology, Women’s Health  \nKeywords Triple-negative breast cancer, PKMYT1, TNF/TRAF1/AKTpathway, Lipid metabolism, Atorvastatin  \nINTRODUCTION  \nBreast cancer (BC) is a heterogeneous disease that can be divided into three primary categories of tumors, including hormone receptor (HR)-positive, HER2-enriched, and triple negative according to the levels of estrogen and progesterone receptors and HER2 amplification or overexpression (Vagia, Mahalingam & Cristofanilli, 2020) . Notably, triple negative breast cancer (TNBC) is characterized by the absence of hormone receptor  \nHow to cite this article Gao W, Guo X, Sun L, Gai J, Cao Y, Zhang S. 2024. PKMYT1 knockdown inhibits cholesterol biosynthesis and promotes the drug sensitivity of triple-negative breast cancer cells to atorvastatin. PeerJ 12:e17749 DOI 10.7717/peerj.17749  \nexpression (ER/PR) and the presence of a high level of human epidermal growth factor (HER2) . Epidemiological evidence indicates that TNBC predominantly presents in women under the age of 40 before menopause, accounting for about 15–20% of all breast cancer cases (Morris et al., 2007; Jiang et al., 2023) . Currently, chemotherapy is the major systemic therapy, but the efficacy of conventional postoperative adjuvant radiotherapy is poor (Zhang et al., 2022) . In addition, some countries use combined used of drugs to treat TNBC. However, patient survival time has not been significantly improved (Wang et al., 2024) . Accordingly, there is a need to actively develop new therapeutic regimens and targets for the treatment of TNBC.  \nMetabolic reprogramming is a hallmark for cancers. Lipids including steroids, isoprenoids, acylglycerols","cbCairg8rpCig9r2","https://ap.wps.com/l/cbCairg8rpCig9r2","pdf",5691079,16,"English","# Abstract\n# Introduction","[{\"question\":\"What is the main finding about PKMYT1 in triple-negative breast cancer (TNBC)?\",\"answer\":\"PKMYT1 is identified as a key driver of cholesterol biosynthesis in TNBC cells, and its aberrant overexpression correlates with unfavorable prognostic outcomes.\"},{\"question\":\"How does PKMYT1 promote cholesterol biosynthesis mechanistically?\",\"answer\":\"PKMYT1 enhances SREBP2-mediated expression of cholesterol biosynthesis enzymes by activating the TNF/TRAF1/AKT signaling pathway.\"},{\"question\":\"What is the effect of PKMYT1 knockdown on statin-mediated cholesterol synthesis and atorvastatin sensitivity?\",\"answer\":\"Downregulating PKMYT1 significantly inhibits feedback upregulation of cholesterol biosynthesis induced by statins, while PKMYT1 knockdown increases the drug sensitivity of TNBC cells to atorvastatin.\"}]","PKMYT1 knockdown inhibits cholesterol biosynthesis and promotes the drug sensitivity of triple-negative breast cancer cells to atorvastatin | PDF",1789990935]