Role of the Histone Modifier KDM2A in Lung Cancer

组蛋白修饰剂 KDM2A 在肺癌中的作用

基本信息

批准号：
9978728
负责人：
Min Gyu Lee
金额：
$ 36.6万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9978728
关键词：
Affect Binding Sites Cancer Etiology Cancer Patient Cancer cell line Cancerous Cell Line Cell Proliferation Cells Cessation of life ChIP-seq Characteristics Chromatin Complement Development Drug Targeting Dual Specificity Phosphatase 3 Epigenetic Process Gene Expression Regulation Genes Genetic Genetic Transcription Genetically Engineered Mouse Goals Histone H3 Histone-Lysine N-Methyltransferase Histones KRAS2 gene Lung Lung Adenocarcinoma Lung Neoplasms Lysine MAPK3 gene Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic Neoplasm to the Lung Methods Methylation Modeling Modification Molecular Mus Mutate Mutation Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Oncogenic Pathogenicity Pathway interactions Phosphoric Monoester Hydrolases Phosphotransferases Proteins Reader Reporting Repression Role Signal Pathway Signal Transduction Solid Survival Rate TP53 gene Therapeutic Therapeutic Agents Transcriptional Regulation Tumor Suppressor Genes Tumorigenicity WNT Signaling Pathway Xenograft Model base beta catenin cancer cell cancer therapy cohort demethylation epigenetic marker epigenetic regulation epigenetic therapy epigenome epigenomics gene repression genetic corepressor genome-wide histone demethylase histone methylation histone methyltransferase improved in vivo inhibitor/antagonist insight knock-down lung tumorigenesis mouse model mutant novel novel therapeutics outcome forecast overexpression prognostic programs small molecule inhibitor success targeted treatment transcriptome sequencing tumor tumorigenesis tumorigenic

项目摘要

PROJECT SUMMARY Lung cancer is the leading cause of cancer death in the US and worldwide. Non-small cell lung cancer (NSCLC) accounts for as much as 85% of all lung cancer cases. The five year survival rate (16%) of NSCLC patients is among the lowest in all malignancies and has not been significantly improved over the past three decades. Histone lysine (K) methylation is considered a hallmark of transcriptional and epigenetic regulation of gene expression. This modification is dynamically controlled by histone methylation modifiers, i.e., histone lysine methyltransferases (methylation writers) and demethylases (methylation erasers). In contrast to great advances in our understanding of kinase signaling pathways, the pathogenic roles of histone methylation modifiers in NSCLC are largely unknown. In our search to identify histone methylation modifiers with oncogenic function for NSCLC, we recently found that in NSCLC tumors, the histone H3 lysine 36 (H3K36) demethylase KDM2A (also known as FBXL11 and JHDM1A) is frequently overexpressed. Our results showed that KDM2A knockdown strongly inhibited tumorigenic and metastatic abilities of KDM2A-high NSCLC cells in mouse xenograft models and that overexpression of KDM2A promoted the proliferation and invasion of KDM2A-low NSCLC cells. The long-term goal is to define the role of the histone modifier KDM2A in lung tumorigenicity. Our additional results revealed that KDM2A repressed tumor-suppressive genes, such as the dual-specificity phosphatase 3 (DUSP3). They also indicate that KDM2A enhances ERK1/2 signaling important for cell proliferation and invasion by epigenetically down-regulating the ERK1/2 phosphatase DUSP3. High KDM2A levels were correlated with poor prognosis in two distinct NSCLC patient cohorts, indicating that KDM2A is a novel poor prognostic epigenetic marker. Based on these definitive findings, our central hypothesis is that KDM2A promotes NSCLC by epigenetically repressing tumor suppressor genes via cooperation with KDM2A-associated protein (s). In the proposed study, we seek to understand the role of KDM2A in lung tumorigenicity using molecular mechanistic studies, genome-wide chromatin sequencing approaches, and our new genetic mouse models. Genetically engineered mouse models proposed here would provide in vivo insights into how KDM2A promotes NSCLC. In addition, our studies promise to uncover new cancer-epigenetic mechanisms by which KDM2A promotes lung cancer and will offer a rationale for the development of a KDM2A-targeted therapy as a new epigenetic therapeutic approach for the treatment of a substantial subset of NSCLC patients.

项目概要肺癌是美国和全世界癌症死亡的主要原因。非小细胞肺癌 (NSCLC) 占所有肺癌病例的 85%。 NSCLC的五年生存率（16%）患者的患病率是所有恶性肿瘤中最低的，并且在过去三年中没有明显改善几十年。组蛋白赖氨酸 (K) 甲基化被认为是转录和表观遗传调控的标志基因表达。这种修饰是由组蛋白甲基化修饰剂动态控制的，即组蛋白赖氨酸甲基转移酶（甲基化写入酶）和去甲基化酶（甲基化擦除器）。与伟大相反我们对激酶信号通路、组蛋白甲基化的致病作用的理解取得了进展 NSCLC 中的修饰因子很大程度上是未知的。在我们寻找组蛋白甲基化修饰剂的过程中 NSCLC 的致癌功能，我们最近发现在 NSCLC 肿瘤中，组蛋白 H3 赖氨酸 36 (H3K36) 去甲基酶 KDM2A（也称为 FBXL11 和 JHDM1A）经常过表达。我们的结果显示 KDM2A 敲低强烈抑制 KDM2A 高 NSCLC 细胞的致瘤和转移能力小鼠异种移植模型中，KDM2A 的过度表达促进了细胞的增殖和侵袭。 KDM2A-低 NSCLC 细胞。长期目标是确定组蛋白修饰剂 KDM2A 在肺中的作用致瘤性。我们的额外结果显示 KDM2A 抑制肿瘤抑制基因，例如双特异性磷酸酶 3 (DUSP3)。他们还表明 KDM2A 增强 ERK1/2 信号传导非常重要通过表观遗传学下调 ERK1/2 磷酸酶 DUSP3 来促进细胞增殖和侵袭。高的 KDM2A 水平与两个不同 NSCLC 患者队列中的不良预后相关，表明 KDM2A 是一种新型的不良预后表观遗传标记。根据这些明确的调查结果，我们的中央假设 KDM2A 通过表观遗传抑制肿瘤抑制基因来促进 NSCLC 与 KDM2A 相关蛋白合作。在拟议的研究中，我们试图了解使用分子机制研究、全基因组染色质测序研究 KDM2A 在肺部致瘤性中的作用方法，以及我们新的基因小鼠模型。这里提出的基因工程小鼠模型将提供有关 KDM2A 如何促进 NSCLC 的体内见解。此外，我们的研究有望发现新的 KDM2A 促进肺癌的癌症表观遗传机制，将为以下研究提供理论依据：开发 KDM2A 靶向疗法作为一种新的表观遗传治疗方法，用于治疗 NSCLC 患者的重要子集。