Chouhan Surbhi, Kumar Anil, Muhammad Naoshad, Usmani Darksha, Khan Tabish H
Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX 75235, USA.
Cecil H and Ida Green Center for Systems Biology, UT Southwestern Medical Center, Dallas, TX 75235, USA.
Cancers (Basel). 2024 Dec 6;16(23):4095. doi: 10.3390/cancers16234095.
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 in curbing 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 angiogenesis, EMT, and metastasis, represent additional targets, with modulators of SIRT6, such as JYQ-42, showing potential to reduce tumor invasiveness. This review aims to provide a comprehensive exploration of the emerging roles of sirtuins, a family of NAD-dependent enzymes, as critical regulators within the oncogenic landscape of pancreatic cancer. This review meticulously explores the nuanced involvement of sirtuins in pancreatic cancer, elucidating their contributions to tumorigenesis and suppression through mechanisms such as metabolic reprogramming, the maintenance of genomic integrity and epigenetic modulation. Furthermore, it emphasizes the urgent need for the development of targeted therapeutic interventions aimed at precisely modulating sirtuin activity, thereby enhancing therapeutic efficacy and optimizing patient outcomes in the context of pancreatic malignancies.
胰腺导管腺癌（PDAC）是最致命的癌症之一，其特点是进展迅速、具有明显的化疗耐药性，以及存在复杂的基因和表观遗传失调网络。在这一具有挑战性的背景下，沉默调节蛋白（sirtuins）作为一类依赖烟酰胺腺嘌呤二核苷酸（NAD）的去乙酰化酶，已成为驱动胰腺癌进展的关键细胞过程的重要调节因子。每种沉默调节蛋白对PDAC的发病机制都有独特的贡献。SIRT1通过缺氧影响细胞凋亡和化疗耐药性，增强糖酵解代谢和缺氧诱导因子-1α（HIF-1α）信号传导，从而维持肿瘤细胞对吉西他滨等药物的存活能力。相反，SIRT2通过抑制真核翻译起始因子5A（eIF5A）来破坏癌细胞增殖，而SIRT3则通过调节线粒体活性氧（ROS）和糖酵解发挥肿瘤抑制作用。SIRT4抑制有氧糖酵解，其治疗性上调已显示出抑制PDAC进展的前景。此外，SIRT5调节谷氨酰胺和谷胱甘肽代谢，为破坏PDAC的代谢依赖性提供了一条途径。SIRT6和SIRT7通过其在血管生成、上皮-间质转化（EMT）和转移中的作用，成为额外的靶点，SIRT6的调节剂，如JYQ-42，显示出降低肿瘤侵袭性的潜力。本综述旨在全面探讨沉默调节蛋白家族（一类依赖NAD的酶）在胰腺癌致癌环境中作为关键调节因子的新出现的作用。本综述精心探讨了沉默调节蛋白在胰腺癌中的细微参与，通过代谢重编程、基因组完整性维持和表观遗传调控等机制，阐明了它们对肿瘤发生和抑制的贡献。此外，它强调迫切需要开发针对性的治疗干预措施，以精确调节沉默调节蛋白的活性，从而在胰腺恶性肿瘤的背景下提高治疗效果并优化患者预后。
