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Sirtuins, NAD+-dependent deacetylases, regulate essential cellular programs that shape PDAC development. Distinct sirtuin functions include SIRT1-mediated survival and chemoresistance via hypoxia, SIRT2 control of proliferation, and SIRT3 regulation of mitochondrial ROS and glycolysis. SIRT4 suppresses aerobic glycolysis, SIRT5 reshapes glutamine and glutathione metabolism, while SIRT6 and SIRT7 influence angiogenesis, EMT, and metastasis. This review highlights sirtuins as potential therapeutic targets for improved drug responses and patient outcomes.",{"@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/sirtuins-as-key-regulators-in-pancreatic-cancer-insights-into-signaling-mechanisms-and-therapeutic-implications/332856/",{"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/sirtuins-as-key-regulators-in-pancreatic-cancer-insights-into-signaling-mechanisms-and-therapeutic-implications/332856.png","ImageObject",300,407,{"name":92,"@type":93},"Clementine","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-09","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",13,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is pancreatic ductal adenocarcinoma (PDAC) considered one of the most lethal cancers?","Question",{"text":113,"@type":114},"PDAC shows rapid progression, early metastasis, and a highly immunosuppressive microenvironment, with a five-year survival rate under 10%. Intrinsic resistance to apoptosis and quick acquisition of chemoresistance limit effectiveness of conventional therapies.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What roles do different sirtuins play in PDAC progression?",{"text":118,"@type":114},"The review assigns distinct functions to individual sirtuins: SIRT1 supports survival and chemoresistance through hypoxia-related pathways, SIRT2 disrupts proliferation, and SIRT3 regulates mitochondrial ROS and glycolysis. It also links SIRT4 to aerobic glycolysis inhibition, SIRT5 to glutamine and glutathione metabolism, and SIRT6/SIRT7 to angiogenesis, EMT, and metastasis.",{"name":120,"@type":111,"acceptedAnswer":121},"How could targeting sirtuin activity benefit PDAC treatment?",{"text":122,"@type":114},"By specifically modulating sirtuin activity, therapies may disrupt PDAC survival mechanisms and metabolic dependencies. This could improve drug responses, reduce tumor aggressiveness, and offer more effective treatment options for patients with challenging pancreatic malignancies.","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},332856,1790325340,{"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},1374391974564,"https://ap-avatar.wpscdn.com/avatar/14000253aa45c000a9e?x-image-process=image/resize,m_fixed,w_180,h_180&k=1779874745381141002","Review  \nSirtuins as Key Regulators in Pancreatic Cancer: Insights into Signaling Mechanisms and Therapeutic Implications  \nSurbhi Chouhan 1,2, *, Anil Kumar 3, Naoshad Muhammad 4, Darksha Usmani 5 and Tabish H. Khan 6  \nCitation: Chouhan, S.; Kumar, A.; Muhammad, N.; Usmani, D.; Khan, T.H. Sirtuins as Key Regulators in Pancreatic Cancer: Insights into Signaling Mechanisms and Therapeutic Implications. Cancers 2024, 16, 4095. [https://doi.org/](https://doi.org/)[ ](https://doi.org/)[10.3390/cancers16234095](10.3390/cancers16234095)  \nAcademic Editor: Atsushi Masamune  \nReceived: 15 November 2024  \nRevised: 4 December 2024  \nAccepted: 5 December 2024  \nPublished: 6 December 2024  \nCopyright: © 2024 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://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75235, USA  \n2 Cecil H and Ida Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, TX 75235, USA  \n3 Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA  \n4 Department of Radiation Oncology, School of Medicine, Washington University, St. Louis, MO 63130, USA  \n5 Department of Ophthalmology, Washington University School of Medicine, St. Louis, MO 63130, USA  \n6 Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63130, USA  \n* Correspondence: surbhi.chouhan@utsouthwestern.edu or [surbhichouhan@gmail.com](surbhichouhan@gmail.com)  \n[Simple Summary:](Simple Summary: Pancreatic ductal adenocarcinoma)[ Pancreatic ductal adenocarcinoma](Simple Summary: Pancreatic ductal adenocarcinoma) ([PDAC](PDAC)) [is a highly aggressive and often deadly](is a highly aggressive and often deadly)[ ](is a highly aggressive and often deadly)[cancer with limited treatment options. Sirtuins](cancer with limited treatment options. Sirtuins), [a group of NAD](a group of NAD)+-dependent enzymes, have recently been identified as key players in PDAC progression and therapy resistance. Each sirtuin has a distinct role in PDAC biology. SIRT1 helps cancer cells survive chemotherapy, SIRT2 inhibits cell growth, and SIRT3 controls mitochondrial health, while SIRT4, SIRT5, SIRT6, and SIRT7 each influence metabolism, angiogenesis, and metastasis. This review explores how these sirtuins contribute to cancer development and highlights their potential as therapeutic targets. By specifically targeting sirtuin activity, new treatments could disrupt PDAC’s survival mechanisms, improve drug responses, and potentially offer more effective options for patients with this challenging cancer.  \nAbstract: Pancreatic ductal adenocarcinoma (PDAC) stands as one of the most lethal cancers, marked by rapid progression, pronounced chemoresistance, and a complex network of genetic and epigenetic dysregulation. Within this challenging context, sirtuins, NAD+-dependent deacetylases, have emerged as pivotal modulators of key cellular processes that drive pancreatic cancer progression. Each sirtuin contributes uniquely to PDAC pathogenesis. SIRT1 influences apoptosis and chemoresistance through hypoxia, enhancing glycolytic metabolism and HIF-1α signaling, which sustain tumor survival against drugs like gemcitabine. SIRT2, conversely, disrupts cancer cell proliferation by inhibiting eIF5A, while SIRT3 exerts tumor-suppressive effects by regulating mitochondrial ROS and glycolysis. SIRT4 inhibits aerobic glycolysis, and its therapeutic upregulation has shown promise incurbing PDAC progression. Furthermore, SIRT5 modulates glutamine and glutathione metabolism, offering an avenue to disrupt PDAC’s metabolic dependencies. SIRT6 and SIRT7, through their roles in angiog","cbCaihGDe9bu3ds3","https://ap.wps.com/l/cbCaihGDe9bu3ds3","pdf",3310382,27,"English","# Introduction\n## Sirtuins and PDAC signaling regulation\n## Therapeutic implications of targeting sirtuin activity\n## Conclusion","[{\"question\":\"Why is pancreatic ductal adenocarcinoma (PDAC) considered one of the most lethal cancers?\",\"answer\":\"PDAC shows rapid progression, early metastasis, and a highly immunosuppressive microenvironment, with a five-year survival rate under 10%. Intrinsic resistance to apoptosis and quick acquisition of chemoresistance limit effectiveness of conventional therapies.\"},{\"question\":\"What roles do different sirtuins play in PDAC progression?\",\"answer\":\"The review assigns distinct functions to individual sirtuins: SIRT1 supports survival and chemoresistance through hypoxia-related pathways, SIRT2 disrupts proliferation, and SIRT3 regulates mitochondrial ROS and glycolysis. It also links SIRT4 to aerobic glycolysis inhibition, SIRT5 to glutamine and glutathione metabolism, and SIRT6/SIRT7 to angiogenesis, EMT, and metastasis.\"},{\"question\":\"How could targeting sirtuin activity benefit PDAC treatment?\",\"answer\":\"By specifically modulating sirtuin activity, therapies may disrupt PDAC survival mechanisms and metabolic dependencies. This could improve drug responses, reduce tumor aggressiveness, and offer more effective treatment options for patients with challenging pancreatic malignancies.\"}]","Sirtuins as Key Regulators in Pancreatic Cancer - Insights into Signaling Mechanisms and Therapeutic Implications | PDF",1789999778,68]