G-quadruplex in Translational Regulation and Cancer Therapy

G-四联体在翻译调控和癌症治疗中的应用

• 批准号: 8357041
• 负责人: HONG LU
• 金额: $ 19.52万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8357041
• 关键词: 5' Untranslated Regions; Abbreviations; Address; Antineoplastic Agents; Area; Binding; Bioinformatics; CCAAT-Enhancer-Binding Proteins; Cancer Patient; Cause of Death; Cell physiology; Chemicals; DNA; Data; Development; Differentiation Therapy; Disease; Foundations; Functional disorder; G-Quartets; Genes; Genetic Transcription; Goals; Grant; Hepatocarcinogenesis; Hepatocyte; Human; Incidence; Knowledge; Ligands; Literature; Liver; Liver Cirrhosis; Liver Fibrosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Normal Cell; Oncogenes; Oncogenic; Physiology; Play; Polyamines; Porphyrins; Primary carcinoma of the liver cells; Protein C; Proteins; Reporting; Resistance; Role; Solid; Testing; Toxic effect; Translational Regulation; Translations; Tumor Suppressor Genes; Tumor Suppressor Proteins; United States; Work; analog; cancer cell; cancer therapy; cytotoxic; design; hepatic nuclear factor 1; histone deacetylase 3; human NCOR1 protein; improved; innovation; killings; liver function; novel; novel strategies; nucleic acid structure; promoter; protein expression; protoporphyrin IX; restoration; small molecule; transcription factor

DESCRIPTION (provided by applicant): The long term goal is to develop novel therapy for liver cancer through simultaneously treating liver cancer and improving liver function, because most liver cancer patients have liver cirrhosis. A group of liver-enriched transcription factors (TFs) are master regulators of liver development and liver function, and they are tumor- suppressors down-regulated during liver carcinogenesis. Literature reports strongly suggest that restoration of the master regulator HNF4? can treat not only liver cancer, but also liver fibrosis. However, like many important oncogenes and tumor-suppressors, HNF4? is a TF that lacks known activating ligand; how to modulate "undruggable" TFs to treat cancer is a huge challenge. Chemicals have been developed to silence "undruggable" oncogenes via stabilizing a special nucleic acid structure, G-quadruplex (G4) in gene promoter. However, the lack of selectivity of G4-stabilizing chemicals toward normal cells is a bottleneck in developing G4-stabilizing chemicals as novel anticancer drugs. Our preliminary data strongly suggest that G4 motif within 5' untranslated region (UTR) is critical in suppressing protein translation of HNF4? and certain liver- enriched essential TFs. The objective of this proposal is to elucidate the importance of G4 motif within 5' UTR in translational regulation of liver-enriched TFs and cancer therapy. The central hypothesis is that G4 motifs in 5' UTR of these master regulators play a key role in suppressing their protein expression. Thus, we can increase protein expression of these master regulators using small molecules or G4 DNA oligos to destabilize G4 within 5' UTR or competitively inhibit G4-interacting proteins. This will be an exciting innovative approach to trea liver cancer and improve liver function simultaneously. This central hypothesis will be tested in 3 specific aims. Aim 1 will determine mechanism of suppression of protein expression of HNF4?1 by its 5' UTR. The working hypothesis is that formation of G4 motif within 5' UTR is essential in inhibiting protein expression. Aim 2 will determine role of G4 motif within 5' UTR of human HNF1?, HNF3?, C/EBP?, C/EBP?, HDAC3, NCOR1, and p53 in regulating protein expression. The working hypothesis is that G4 motif within 5' UTR is essential in suppressing protein expression of these TFs. Aim 3 will determine effects of G4-interacting chemicals and G4 oligos from 5' UTR of above 8 human TFs on protein expression of these TFs. The working hypothesis is that TMPYP4, polyamines, and protoporphyrin IX inhibits, whereas certain G4 DNA oligos increase protein expression of these TFs in hepatoma/hepatocytes. This study is highly novel, because it is the first to address the importance of an important nucleic acid structure, G4 in regulating the protein expression of a group of essential liver-enriched TFs. This study is highly significant, because results from this study will not only provide important novel knowledge, but also greatly aid the rational design of G4- interacting anticancer drugs, and help to develop a paradigm-shift approach to coordinately target otherwise "undruggable" essential liver-enriched TFs to simultaneously treat liver cancer and improve liver function. PUBLIC HEALTH RELEVANCE: The United States has increasing incidence of liver cancer, a deadly disease that is the 3rd leading cause of death from cancer worldwide. The proposed studies are of importance in the under-investigated area of how the protein expression of master regulators of liver pathophysiology is regulated by a special nucleic acid structure, G-quadruplex, which is a potential novel target for anticancer drugs. Thus, the findings are expected to enhance our understanding of liver diseases and liver cancer, and this knowledge can be used to develop novel approaches to target otherwise "undruggable" essential oncogenes and tumor-suppressors to treat liver cancer and liver diseases.

描述（由申请人提供）：长期目标是通过同时治疗肝癌和改善肝功能来开发肝癌的新疗法，因为大多数肝癌患者患有肝性肝硬化。一组富含肝脏的转录因子（TFS）是肝发育和肝功能的主要调节剂，它们是肝癌发生过程中下调的肿瘤抑制剂。文献报道强烈建议恢复主监管机HNF4？不仅可以治疗肝癌，还可以治疗肝纤维化。 但是，像许多重要的癌基因和肿瘤抑制剂HNF4一样？是缺乏已知激活配体的TF；如何调节“不难”的TF来治疗癌症是一个巨大的挑战。已经开发出化学物质是通过稳定基因启动子中特殊的核酸结构，G Quadruplex（G4）来沉默的“不可能”的癌基因。但是，G4稳定化学物质对正常细胞缺乏选择性是开发G4稳定化学物质作为新型抗癌药物的瓶颈。我们的初步数据强烈表明，在5'未翻译区域（UTR）内的G4基序对于抑制HNF4的蛋白质翻译至关重要？和某些富含肝脏的必需TF。该提案的目的是阐明在5'UTR中G4基序在富含肝脏富含TFS和癌症治疗的转化调节中的重要性。中心假设是，这些主调节剂的5'UTR中的G4基序在抑制其蛋白质表达方面起着关键作用。因此，我们可以使用小分子或G4 DNA寡聚来增加这些主调节剂的蛋白质表达，从而在5'UTR内不稳定G4或竞争性抑制G4相互作用的蛋白质。这将是一种令人兴奋的创新方法，可同时改善肝癌并改善肝功能。该中心假设将在3中进行检验 具体目标。 AIM 1将通过其5'UTR来确定HNF4？1抑制蛋白表达的机制。工作假设是，在5'UTR中的G4基序的形成对于抑制蛋白质表达至关重要。 AIM 2将确定G4基序在人Hnf1的5'UTR中的作用，hnf3？，c/eBP？，c/eBP？，hdac3，ncor1和p53在调节蛋白质表达中。工作假设是5'UTR中的G4基序对于抑制这些TF的蛋白质表达至关重要。 AIM 3将确定来自5'UTR的G4相互作用化学物质和G4寡素对这些TF的蛋白质表达的影响。工作假设是TMPYP4，多胺和原源性IX抑制，而某些G4 DNA寡素会增加肝癌/肝细胞中这些TF的蛋白质表达。这项研究是高度新颖的，因为它是第一个解决重要核酸结构的重要性的G4，它在调节一组富含肝脏的TFS的蛋白质表达方面。这项研究非常重要，因为这项研究的结果不仅将提供重要的新知识，而且还极大地帮助了G4相互作用的抗癌药物的合理设计，并有助于开发一种范式偏移方法，以协调针对其他“不可用”必不可少的肝脏含量的TF，以同时治疗肝癌和肝癌。 公共卫生相关性：美国的肝癌发病率越来越高，这是一种致命的疾病，是全球癌症的第三大死亡原因。拟议的研究在不足的领域非常重要，即如何通过特殊的核酸结构G-四方链体调节肝脏病理生理学的主要调节剂的蛋白质表达，这是抗癌药物的潜在新型靶标。因此，这些发现有望增强我们对肝病和肝癌的理解，并且这些知识可用于开发新的方法，以靶向其他“不受限制”的必需癌基因和肿瘤抑制剂，以治疗肝癌和肝脏疾病。