Role of IKK in NSCLC: Modulation of SMRT and NF-kappaB

IKK 在 NSCLC 中的作用：SMRT 和 NF-κB 的调节

• 批准号: 8193250
• 负责人: MARTY W MAYO
• 金额: $ 27万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-19 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193250
• 关键词: Acetylation; Address; American; Architecture; Biomedical Research; Breast; Breast Cancer Cell; Carcinoma; Cell-Cell Adhesion; Cells; Characteristics; Clinical; Colorectal; Complex; Data; Detection; Diagnosis; Diagnostic Neoplasm Staging; Disease; Distant; Ensure; Epigenetic Process; Gene Activation; Gene Expression; Gene Expression Microarray Analysis; Gene Targeting; Genes; Genetic Transcription; Goals; HDAC3 gene; Health; Histone H3; Histones; Human; Invaded; Laboratories; Lead; Link; Liver; Lung; Lysine; Maintenance; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator of activation protein; Mesenchymal; Modeling; Modification; Morphogenesis; Morphology; NF-kappa B; Neoplasm Metastasis; Newly Diagnosed; Non-Small-Cell Lung Carcinoma; Outcome; PCAF gene; Patients; Phenotype; Play; Polycomb; Process; Prostate; Proteins; Recruitment Activity; Regulation; Retinoids; Role; Seeds; Site; Snails; Staging; Stem cells; System; TNF gene; Thyroid Hormone Receptor; Time; Tumor Tissue; Tumor stage; United States; Work; bone; cancer cell; cancer initiation; cancer stem cell; epigenomics; epithelial to mesenchymal transition; genome-wide analysis; histone deacetylase 3; melanoma; migration; mouse model; new therapeutic target; novel; outcome forecast; p65; prevent; promoter; protein complex; protein expression; slug; stem; transcription factor; tumor; tumor progression

DESCRIPTION (provided by applicant): Lung cancer is the number one cancer killer in the United States, exceeding breast, colorectal, prostate, and melanoma malignancies combined. Of all newly diagnosed lung cancers, greater than eighty percent of these malignancies are non-small cell lung cancer (NSCLC). NF-?B is a transcription factor that plays a key role in the activation of genes involved in cancer initiation and progression. NF-?B activity in human tumors is associated with dedifferentiated NSCLC morphology, advanced tumor stage, and poor clinical outcomes. The tumor microenvironment is responsible for stimulating a morphogenesis within carcinoma cells referred to as epithelial to mesenchymal transition (EMT). EMT is believed to be essential to carcinoma progression by stimulating invasion and metastasis. Although NF-?B has been shown to be required for EMT, the importance of this regulation is poorly understood. Our laboratory has developed a novel EMT system that allows NSCLC cells to achieve 100% transition. Induction of EMT in NSCLC cells greatly increases migration, invasion, and lung metastasis, resulting in constitutive NF-?b transcriptional activity. Inhibition of NF-?B prevents NSCLC cells from undergoing EMT, indicating that NF-?B plays a direct role in the EMT process. The induction of EMT stimulates the expression of master-switch transcription factors, including Twist, and increases the expression of the polycomb repressive complex (PRC) proteins, which are critical for initiation and maintenance of stem-like phenotypes. Mesenchymal NSCLC cells require NF-?B to upregulate critical components of the PRC, while differentially repressing others. NF-?B stimulates gene expression of PRC proteins by recruiting IKK1 and PCAF to responsive promoters and derepressing SMRT (silencing mediator for retinoid and thyroid hormone receptors) and histone deacetylase (HDAC)3 corepressor complexes. In contrast, Twist and NF-?B actively repress other gene targets by stable recruitment of SMRT/HDAC3. Here, we provide the first evidence associating NF-?B with an increase in epigenetic modifications associated with cancer progenitor cells. The main goal of this proposal is to identify NF-?B regulated genes that encode epigenetic effectors responsible for initiating reprogramming of cancer progenitor cells. To address our hypothesis, three specific aims will be addressed. Aim 1 will identify NF-?B regulated genes that coordinate epigenetic reprogramming in cancer progenitor cells using genome-wide analysis. Aim 2 will determine the role of p65 as an activator or repressor of polycomb-mediated gene expression. Aim 3 will examine the role of NF-?B in epigenetic reprogramming using human tumor tissues and lung metastasis models. Identifying the importance of NF-?B in regulating key factors that govern epigenetic reprogramming in cancer progenitor cells will potentially lead to the discovery of novel therapeutic targets for the diagnosis and treatment of lung cancer. PUBLIC HEALTH RELEVANCE: A major focus in biomedical research is to understand how cancer cells invade healthy cells and metastasize to distant sites. Lung cancer in particular is more prone to aggressive forms of the disease that are difficult to treat effectively and have a poor clinical prognosis. Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. The 5-year mean survival for patients suffering from stage III lung cancer is less than 30%. Poor clinical prognosis for NSCLC is directly associated with late-stage diagnosis and high propensity for metastasis to liver and bone. For the last several years our laboratory has been working on a transcription factor called nuclear factor-kappa B (NF-?B). NF-?B is a protein complex that is found in almost all human cells. In non-cancerous cells NF-?B is tightly regulated, however, cancer cells have found ways to elevate the activity of NF-?B. Although it is known that cancer cells enhance NF-?B activity, the reasons for this are not fully understood. Our laboratory has discovered that NF-?B is one of the master-switch transcription factors required to induce phenotypic changes in cells referred to as epithelial to mesenchymal transition (EMT). EMT is a critical step in cancer metastasis. For the first time, our laboratory can demonstrate that following the induction of EMT, NF-?B is required to orchestrate changes associated with the induction and maintenance of cancer stem cells. Cancer stem cells are believed to act as a "seed" which is able to reestablish malignant disease. This proposal will identify critical EMT-induced genes that are required for induction and maintenance of cancer stem cells. The overall goal of this project is use these newly identified gene products as novel therapeutic targets for detection and treatment of NSCLC.

描述（由申请人提供）：肺癌是美国排名第一的癌症杀手，超过乳腺癌，结直肠癌，前列腺和黑色素瘤恶性肿瘤。在所有新诊断的肺癌中，这些恶性肿瘤中有超过80％是非小细胞肺癌（NSCLC）。 NF-？B是转录因子，在癌症启动和进展的基因激活中起关键作用。人类肿瘤中的NF-？B活性与去分化的NSCLC形态，晚期肿瘤阶段和临床结局差有关。肿瘤微环境负责刺激癌细胞内的形态发生，称为间质转变（EMT）。据信EMT通过刺激侵袭和转移而对癌的进展至关重要。尽管已证明NF-？b是EMT所需的，但该法规的重要性知之甚少。我们的实验室开发了一种新型的EMT系统，该系统允许NSCLC细胞实现100％的过渡。 NSCLC细胞中EMT的诱导大大增加了迁移，侵袭和肺转移，从而导致构成NF-？B转录活性。 NF-？B的抑制可防止NSCLC细胞进行EMT，表明NF-？B在EMT过程中起着直接的作用。 EMT的诱导刺激了主开关转录因子的表达，包括扭曲，并增加了多孔抑制复合物（PRC）蛋白的表达，这对于启动和维持茎样表型至关重要。间充质NSCLC细胞需要NF-？b上调PRC的关键组成部分，同时差异化抑制他人。 NF-？b通过募集IKK1和PCAF来刺激PRC蛋白的基因表达，并为反应性启动子募集并对SMRT（视视视视认为和甲状腺激素受体的沉默介质）和组蛋白脱乙酰基酶（HDAC）（HDAC）3核心配合物。相比之下，扭曲和NF-？b通过稳定的SMRT/HDAC3募集来积极抑制其他基因靶标。在这里，我们提供了第一个将NF- b的证据与与癌症祖细胞相关的表观遗传修饰增加的证据。该提案的主要目标是识别编码负责启动癌症祖细胞重编程的表观遗传效应子的NF- b调节基因。为了解决我们的假设，将解决三个具体目标。 AIM 1将通过全基因组分析来鉴定NF-？B调节的基因，以在癌症祖细胞中进行表观遗传重编程。 AIM 2将确定p65作为多肉体介导的基因表达的激活剂或阻遏物的作用。 AIM 3将检查NF-？B在使用人肿瘤组织和肺转移模型的表观遗传重编程中的作用。确定NF-？B在调节癌症祖细胞中表观遗传重编程的关键因素中的重要性可能会导致发现新的治疗靶标在诊断和治疗肺癌。公共卫生相关性：生物医学研究的主要重点是了解癌细胞如何侵入健康的细胞并转移到遥远的部位。尤其是肺癌更容易受到侵略性形式的疾病，这些疾病难以有效治疗并且临床预后较差。非小细胞肺癌（NSCLC）是最常见的肺癌形式。患有III期肺癌患者的5年平均存活率小于30％。 NSCLC的临床预后不良与后期诊断和对肝脏和骨骼转移的高倾向直接相关。在过去的几年中，我们的实验室一直在研究称为核因子-kappa B（NF-？b）的转录因子。 NF-？B几乎在所有人类细胞中都发现了蛋白质复合物。但是，在非癌细胞中，NF-？B受到严格调节，但是，癌细胞已经找到了提高NF- b的活性的方法。尽管众所周知，癌细胞增强了NF-？b活性，但其原因尚未完全理解。我们的实验室发现NF-？B是诱导被称为间质转变（EMT）上皮的细胞中表型变化所需的主开关转录因子之一。 EMT是癌症转移的关键一步。我们的实验室第一次可以证明，在诱导EMT之后，需要进行NF-？B，以协调与癌症干细胞诱导和维持相关的变化。据信癌症干细胞充当能够重建恶性疾病的“种子”。该建议将确定癌症干细胞诱导和维持所需的关键EMT诱导的基因。该项目的总体目标是将这些新鉴定的基因产品用作检测和治疗NSCLC的新型治疗靶标。