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

基本信息

批准号：
8494599
负责人：
HONG LU
金额：
$ 16.3万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-01 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8494599
关键词：
5&apos 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

项目摘要

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.

描述（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硬化。一组富含肝脏的转录因子（TF）是肝脏发育和肝功能的主要调节因子，并且它们是肝癌发生过程中下调的肿瘤抑制因子。文献报道强烈建议恢复主调节器HNF4？不仅可以治疗肝癌，还可以治疗肝纤维化。然而，像许多重要的癌基因和肿瘤抑制基因一样，HNF4？是缺乏已知激活配体的转录因子；如何调节“不可成药”的TF来治疗癌症是一个巨大的挑战。化学物质已被开发出来，通过稳定基因启动子中的特殊核酸结构 G-四链体 (G4) 来沉默“不可成药”的癌基因。然而，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 5' 非翻译区 (UTR) 内的 G4 基序对于抑制 HNF4 的蛋白质翻译至关重要？以及某些富含肝脏的必需转录因子。该提案的目的是阐明 5' UTR 内的 G4 基序在肝脏富集 TF 的翻译调节和癌症治疗中的重要性。中心假设是这些主调节因子 5' UTR 中的 G4 基序在抑制其蛋白质表达中发挥着关键作用。因此，我们可以使用小分子或 G4 DNA 寡核苷酸来增加这些主调节因子的蛋白质表达，以破坏 5' UTR 内的 G4 稳定性或竞争性抑制 G4 相互作用蛋白。这将是一种令人兴奋的创新方法，可以同时治疗肝癌和改善肝功能。这个中心假设将在 3 年内得到检验具体目标。目标 1 将确定 HNF4?1 的 5' UTR 抑制蛋白表达的机制。目前的假设是，5'UTR 内 G4 基序的形成对于抑制蛋白质表达至关重要。目标 2 将确定人 HNF1?、HNF3?、C/EBP?、C/EBP?、HDAC3、NCOR1 和 p53 5' UTR 内的 G4 基序在调节蛋白质表达中的作用。目前的假设是 5' UTR 内的 G4 基序对于抑制这些 TF 的蛋白质表达至关重要。目标 3 将确定来自以上 8 个人类 TF 的 5' UTR 的 G4 相互作用化学物质和 G4 寡核苷酸对这些 TF 的蛋白质表达的影响。工作假设是 TMPYP4、多胺和原卟啉 IX 会抑制肝癌/肝细胞中这些 TF 的蛋白表达，而某些 G4 DNA 寡核苷酸会增加这些 TF 的蛋白表达。这项研究非常新颖，因为它是第一个解决重要核酸结构 G4 在调节一组必需的肝脏富集 TF 的蛋白质表达中的重要性的研究。这项研究具有非常重要的意义，因为这项研究的结果不仅将提供重要的新知识，而且极大地有助于G4相互作用抗癌药物的合理设计，并有助于开发一种范式转换方法来协调靶向其他“不可成药”的必需药物富含肝脏的转录因子可同时治疗肝癌并改善肝功能。