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.

美国黑色素瘤发病率正在迅速增加，预计 2020 年将有 100,350 例病例。 黑色素瘤是退伍军人的一个严重问题，是五种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。 治疗方法，包括最近批准的 BRAF 抑制剂，尚未对黑色素瘤完全有效 因此，需要新的基于目标的方法。 我们有一个正在进行的研究计划来确定沉默调节蛋白在治疗中的作用。 哺乳动物的 Sirtuins 家族由七个成员组成 (SIRT1 – SIRT7)，发挥着至关重要的作用。 在重要的细胞过程中发挥作用，并与包括癌症在内的多种疾病有关。 癌症中的 SIRT 很复杂，并且根据细胞背景，它们似乎具有二分功能。 研究表明，sirtuin 6 (SIRT6)（一种主要的核蛋白）参与调节涉及的通路 SIRT6 已被发现对基因转录、葡萄糖稳态、DNA 修复和端粒完整性有影响。 抑制肠道和肝脏的肿瘤发生，然而，SIRT6 在皮肤和肝脏中也具有促增殖作用。 前列腺癌，表明其功能可能与组织和环境相关。 还被证明可以调节上皮间质转化（EMT）并促进某些细胞的转移 在最近的一项研究中，我们证明 SIRT6 在人类黑色素瘤细胞中过度表达。 和组织，通过 shRNA 介导的 RNA 干扰抑制 SIRT6 导致显着的抗增殖作用 反应（生长抑制、细胞周期交替、细胞迁移抑制、衰老和自噬 我们的初步数据和已发表的研究以及其他已发表的研究。 研究为我们研究其作用和潜在治疗提供了强有力的科学前提 SIRT6 在黑色素瘤中的重要性并支持我们提出的假设，即 SIRT6 在黑色素瘤中发挥关键作用 黑素细胞转化和黑素瘤进展以及其他驱动途径可以 提出以下具体目标： 1) 定义 SIRT6 在黑色素瘤发生和进展中的作用及其与关键黑色素瘤驱动因素的关联 采用由退伍军人的回顾性黑色素瘤组织创建的组织微阵列 (TMA) 的途径 为此，我们将确定 SIRT6 在黑色素瘤中的作用及其与危重患者的关系。 黑色素瘤通路驱动程序（RAS/RAF/MEK/ERK- 和 p16/cyclin D-CDK4/6-RB- 通路）；2) 确定 SIRT6 在黑色素瘤中的功能和机制意义 为此，我们将确定 SIRT6 的作用。 CRISPR/Cas9 介导 SIRT6 缺失对体外和体内黑色素瘤细胞生长和进展的影响； 3) 确定 SIRT6 单独抑制以及与其他有希望的药物联合抑制的治疗意义 我们将使用小分子药物确定 SIRT6 抑制的效果。 SIRT6 分子抑制剂单独使用以及与其他临床相关黑色素瘤疗法联合使用（BRAF 和 MEK 抑制剂 Trametinib）对黑色素瘤发展、生长和转移的影响 1) Braf-Pten 小鼠模型和 2) 患者来源的异种移植物 (PDX) 我们希望我们的研究能够明确其作用， SIRT6 在黑色素瘤中的机制和相互作用以及临床前环境中的新组合， 这可能对未来的临床研究有用，这可能最终导致新型药物的开发。 因此，我们提出的研究是相关且有效的。 对退伍军人的医疗保健具有重要意义，并且符合退伍军人事务部的使命。