Role of sirtuin 6 in melanoma development and progression

Sirtuin 6 在黑色素瘤发生和进展中的作用

• 批准号: 10595641
• 负责人: Nihal Ahmad
• 金额: --
• 依托单位: WM S. MIDDLETON MEMORIAL VETERANS HOSP
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-10-01 至 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10595641
• 关键词: ADP Ribose Transferases; Apoptosis; Autophagocytosis; BRAF gene; CDK4 gene; CRISPR/Cas technology; Cancer Patient; Cell Cycle; Cell Migration Inhibition function; Cell physiology; Cells; ChIP-seq; Chemicals; Climate; Co-Immunoprecipitations; Complex; Computer software; Coupled; Cyclin D1; DNA Repair; Data; Development; Diagnosis; Disease; Disease Outcome; Doxycycline; E-Cadherin; Epithelium; Exposure to; Family; Fibronectins; Future; Genetic Transcription; Goals; Growth; Growth and Development function; Healthcare; Human; In Vitro; Incidence; Intestines; Invaded; Investigation; Keratin-19; Knock-out; LOX gene; Link; Liver; MEKs; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Melanoma Cell; Mesenchymal; Metabolism; Metastatic Melanoma; Mission; Modality; Modeling; Molecular; Molecular Profiling; Molecular Target; Mus; N-Cadherin; NOD/SCID mouse; Neoplasm Metastasis; Neoplasms; Nevus; Nuclear; Nuclear Protein; Outcome; PET/CT scan; Pathway interactions; Patient-Focused Outcomes; Patients; Play; Process; Proteins; Proteomics; Publishing; RNA Interference; Ras/Raf; Recurrence; Research; Resistance; Role; SIRT1 gene; Salicylic Acids; Sampling; Sir2-like Deacetylases; Sirtuins; Skin; Skin Cancer; Therapeutic; Tissue Microarray; Tissues; United States Department of Veterans Affairs; Validation; Vertebral column; Veterans; Vimentin; Western Blotting; X-Ray Computed Tomography; Xenograft Model; blood glucose regulation; cancer diagnosis; cancer type; clinical investigation; clinically relevant; high risk; imaging platform; improved; in vivo; indexing; inhibitor; knock-down; melanocyte; melanoma; member; migration; mouse model; novel; novel diagnostics; overexpression; patient derived xenograft model; pre-clinical; prognostic; programs; response; senescence; small hairpin RNA; small molecule; telomere; transcriptome sequencing; tumorigenesis; ultraviolet; usability

Melanoma incidences are increasing rapidly with 100,350 cases predicted in 2020 in the US. Further, melanoma is a significant problem in Veterans, and it is among the five most frequently diagnosed cancers among VA cancer patients. Malignant melanoma is one of the deadliest forms of cancer, and the existing therapeutics, including recently approved BRAF inhibitors, have not been fully effective in melanoma management due to acquired resistance. Therefore, novel target-based approaches are needed for the management of this neoplasm. We have an ongoing research program to define the role of sirtuins in melanoma. The mammalian sirtuins constitute a family of seven members (SIRT1 – SIRT7), which play critical roles in important cellular processes, and are involved in a variety of diseases, including cancer. The role of SIRTs in cancer is complex, and they appear to have dichotomous functions depending on cell context. Recent studies have implicated sirtuin 6 (SIRT6), a predominantly nuclear protein, in regulating pathways involved in gene transcription, glucose homeostasis, DNA repair and telomere integrity. SIRT6 has been found to suppress tumorigenesis in the intestine and liver. However, SIRT6 also has a pro-proliferative role in skin and prostate cancer, suggesting that its function may be tissue- and context- dependent. Interestingly, SIRT6 has also been shown to modulate epithelial-mesenchymal transition (EMT) and promote metastasis in certain cancer types. In a recent study, we have demonstrated that SIRT6 is overexpressed in human melanoma cells and tissues, and SIRT6 inhibition via shRNA-mediated RNA interference resulted in a marked antiproliferative response (growth inhibition, cell cycle alternation, inhibition of cell migration, senescence and autophagy dysregulation) in melanoma cells. Our preliminary data and published study together with other published research provide a strong scientific premise to our investigation into the role and potential therapeutic significance of SIRT6 in melanoma and supports our proposed hypothesis that SIRT6 plays a critical role in melanocytic transformation and melanoma progression and together with other driver pathways, can be therapeutically exploited for melanoma management. The following specific aims are proposed: 1) To define the role of SIRT6 in melanoma development and progression and its association with critical melanoma driver pathways employing a tissue microarray (TMA) created from retrospective melanoma tissues from Veteran patients. In this aim, we will determine the role of SIRT6 in melanoma as well as its association with critical melanoma driver pathways (RAS/RAF/MEK/ERK-, and p16/cyclin D-CDK4/6-RB- pathways); 2) To determine the functional and mechanistic significance of SIRT6 in melanoma. In this aim, we will determine the effect of CRISPR/Cas9 mediated SIRT6 deletion on growth and progression of melanoma cells in vitro and in vivo; and 3) To determine the therapeutic significance of SIRT6 inhibition alone and in combination with other promising target-based anti-melanoma modalities in vivo. We will determine the effects of SIRT6 inhibition using small molecule SIRT6 inhibitor alone and in combination with other clinically relevant melanoma therapies (BRAF inhibitor, Vemurafenib; and MEK inhibitor, Trametinib) on melanoma development, growth and metastasis in 1) Braf-Pten mouse model, and 2) patient-derived xenografts (PDX). We expect that our study will define the role, mechanism, and interactions of SIRT6 in melanoma as well as novel combinations in pre-clinical settings, which could be useful for future clinical investigations. This may ultimately lead to the development of novel diagnostic, prognostic, and therapeutic approaches for melanoma. Hence, our proposed study is relevant and significant to the health care of Veterans and is in line with the mission of the Department of Veteran Affairs.

黑色素瘤发动机正在迅速增加，在2020年预计的100,350例病例中，黑色素瘤的发动机正在迅速增加。更远， 黑色素瘤是退伍军人的重大问题，它是最常诊断的癌症之一 在VA癌症患者中。恶性黑色素瘤是最致命的癌症之一，现有 包括最近批准的BRAF抑制剂在内的治疗尚未完全有效 由于获得了阻力而导致的管理。因此，需要新颖的基于目标的方法 该肿瘤的管理。我们有一个正在进行的研究计划来定义Sirtuins在 黑色素瘤。哺乳动物的sirtuins构成了一个由七个成员（SIRT1 - SIRT7）的家庭，它发挥了关键 在重要的细胞过程中的作用，并参与包括癌症在内的多种疾病。的作用 癌症中的SIRT是复杂的，它们似乎具有二分法功能，具体取决于细胞环境。最近的 研究已经实施了SIRTUIN 6（SIRT6），这是一种主要是核蛋白，用于调节涉及的途径 基因转录，葡萄糖稳态，DNA修复和端粒完整性。已经发现SIRT6 抑制肠和肝脏中的肿瘤发生。但是，SIRT6在皮肤和 前列腺癌，表明其功能可能取决于组织和背景。有趣的是，Sirt6拥有 还显示出调节上皮 - 间质转变（EMT）并在某些人中促进转移 癌症类型。在最近的一项研究中，我们证明了SIRT6在人黑色素瘤细胞中过表达 和组织，以及通过SHRNA介导的RNA干扰的SIRT6抑制作用导致明显的抗增殖 反应（生长抑制，细胞周期替代，抑制细胞迁移，感应和自噬 黑色素瘤细胞的失调）。我们的初步数据并与其他已发表的研究一起发布 研究为我们对角色和潜在疗法的研究提供了强大的科学前提 SIRT6在黑色素瘤中的重要性，并支持我们提出的假设，即SIRT6在 黑色素细胞转化和黑色素瘤的进展以及与其他驱动器通路一起可以是 治疗探索黑色素瘤管理。提出了以下特定目标：1）定义 SIRT6在黑色素瘤发育和进展中的作用及其与关键黑色素瘤驱动器的关联 采用从回顾性黑色素瘤组织中产生的组织微阵列（TMA）的途径 患者。在此目标中，我们将确定SIRT6在黑色素瘤中的作用以及与关键的关联 黑色素瘤驱动器途径（RAS/RAF/MEK/ERK-和P16/CYCLIN D-CDK4/6-RB-途径）; 2）确定 SIRT6在黑色素瘤中的功能和机械意义。在此目标中，我们将确定 CRISPR/CAS9介导了SIRT6的缺失，这些缺失在体外和体内介导了黑色素瘤细胞的生长和进展；和 3）仅确定SIRT6抑制的治疗意义，并与其他承诺结合 基于目标的抗黑色素瘤体内。我们将使用小 分子SIRT6抑制剂并与其他临床相关的黑色素瘤疗法（BRAF）结合使用 抑制剂，vemurafenib; 1） BRAF-PTEN小鼠模型和2）患者衍生的Xenographing（PDX）。我们希望我们的研究将定义角色， SIRT6在黑色素瘤中的机制以及在临床前环境中的新型组合的相互作用， 这对于将来的临床研究可能很有用。这最终可能导致小说的发展 黑色素瘤的诊断，预后和治疗方法。因此，我们提出的研究是相关的， 对退伍军人的卫生保健意义，与退伍军人事务部的任务一致。