Identifying tumor suppressor targets of SIRT6 in lung cancer

鉴定肺癌中 SIRT6 的抑癌靶点

基本信息

批准号：
8913463
负责人：
MARTY W MAYO
金额：
$ 39.63万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-02 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8913463
关键词：
Acetylglucosamine Address Age American Cancer Biology Cancer Etiology Carcinoma Cell physiology Cessation of life Characteristics Chromatin Cleaved cell Clinical Deacetylase Detection Development Diagnosis Disease Enzymes Family Feedback Frequencies Genes Genetic Genetic Transcription Goals HIF1A gene Histones Human Inflammation Link Liver Location Lung Adenocarcinoma Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Metabolic Metabolic Pathway Metabolism Methods Mus N-terminal Neoplasm Metastasis Newly Diagnosed Non-Small-Cell Lung Carcinoma Nutrient O-GlcNAc transferase Pathway interactions Patients Process Production Property Proteins Regulation Resistance Smoking Somatic Mutation Squamous cell carcinoma Staging Survival Rate Therapeutic Intervention Tumor Suppressor Proteins Uridine Diphosphate N-Acetylglucosamine bone c-Myc Staining Method cancer cell cancer type fluorodeoxyglucose positron emission tomography genome-wide glucose uptake improved in vivo inhibitor/antagonist insight killings malignant phenotype member mouse model never smoker novel outcome forecast public health relevance sensor small molecule statistics sugar sugar nucleotide transcription factor tumor tumor growth tumor metabolism

项目摘要

DESCRIPTION (provided by applicant): Each year, lung cancer kills more than 150,000 Americans. Despite this statistic, the 5-year survival for lung cancer has not significantly improved in the past 30 years. The poor clinical prognosis for NSCLC is linked directly to late-stage diagnosis and high frequency of cancer metastasis. Of all newly diagnosed lung cancers, greater than eighty-five percent of these malignancies are non-small cell lung cancer (NSCLC), with patients presenting with disseminated disease. Therefore, a better understanding of the cellular processes that govern NSCLC metastasis is needed for therapeutic intervention. Sirtuin 6 (SIRT6), a member of the Sirtuin family of histone deacetylases, acts to regulate inflammation, ageing and cancer processes. Although SIRT6 is known to regulate metabolic pathways in cancer, how the culmination of these pathways impact tumor growth and metastasis is poorly understood. In this proposal, we provide evidence that expression of SIRT6 is lost in lung adenocarcinomas and correlates with reduced overall patient survival. Using a conditional mouse model, we identified a group of metabolic genes that are co-regulated by SIRT6 and the transcription factor NF-B. Interestingly, these gene products generate building blocks required for the synthesis of the nutrient sensor, UDP-N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the donor sugar nucleotide used to promote O- GlcNAc transferase (OGT) activity; a pathway implicated in cancer metabolism and metastasis. Since SIRT6 represses NF-B transcription, we postulate that the loss of SIRT6 in NSCLC sets up a positive feedback loop by which NF-B drives metabolic reprogramming. Moreover, we find that OGT is required for the proteolytic cleavage and inactivation of chromatin-associated SIRT6. Our overall hypothesis is that SIRT6 functions as a tumor suppressor to inhibit UDP-GlcNAc synthesis and that misregulation of this nutrient sensor stimulates OGT to inactivate SIRT6. To address this hypothesis two Specific Aims will be addressed. Aim 1 will determine whether the loss of SIRT6 promotes NF-B B-dependent metabolic reprogramming and will identify critical enzymes that are essential for malignant characteristics. Aim 2 will elucidate the significance of N-terminal cleaved SIRT6 on NSCLC development and metastasis. Since clinically approved small molecule inhibitors are available that would block the synthesis of UDP-GlcNAc this application provides novel insight into how combinations of these inhibitors could be repurposed and used for the treatment of NSCLC.

描述（由申请人证明）：在过去的30年中，肺癌150,000名诊断出肺部癌细胞肺癌（NSCLC），患有传播性疾病的患者，对脱乙酰氨的细胞过程有更好的了解。 SIRT6的代谢途径是肺腺癌，与SIRT6共同调节的代谢基因的总体生存率降低。营养传感器，UDP-N-乙酰葡萄糖（UDP-GLCNAC）。反馈循环，NF-B驱动代谢重新编程，我们发现OGT是蛋白质粘膜蛋白的SIRT6所必需的。 . Of this nutrient Sensor Stimulates Ogt to INACTIVATE SIRT6. To Adds This Hypothesis too Specific Aims WILL BE ADRESSSED. WILL DETERMINE ER The Loss of Sirt6 Promotes NF-B-Dependent Metabolic Repromming and Will Identify Critical Enzymes That is Essential for Malignant Characteristics. 2将阐明NSCLC发育和转移的N末端Cleart6。