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.

项目摘要肺癌是美国和全球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％）患者在所有恶性肿瘤中都是最低的，并且在过去的三个中尚未得到显着改善几十年。组蛋白赖氨酸（K）甲基化被认为是转录和表观遗传调节的标志基因表达。这种修饰由组蛋白甲基化修饰剂（即组蛋白）动态控制赖氨酸甲基转移酶（甲基化作者）和脱甲基酶（甲基化橡皮擦）。与伟大相反我们对激酶信号通路的理解进展，组蛋白甲基化的致病作用 NSCLC中的修饰符在很大程度上未知。在我们的搜索中，以识别使用的组蛋白甲基化修饰剂 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。我们的结果表明 KDM2A敲低强烈抑制了KDM2A-HIGH NSCLC细胞中的致瘤和转移能力小鼠异种移植模型以及KDM2A的过表达促进了 KDM2A-LOW NSCLC细胞。长期目标是定义组蛋白修饰剂KDM2A在肺中的作用肿瘤性。我们的其他结果表明，KDM2A抑制了肿瘤抑制基因，例如双特异性磷酸酶3（DUSP3）。他们还表明KDM2A增强了ERK1/2信号的重要通过表观遗传下调ERK1/2磷酸酶dusp3的细胞增殖和侵袭。高的 KDM2A水平与两个不同的NSCLC患者队列中的预后不良相关，表明 KDM2A是一种新颖的预后表观遗传标记。基于这些确定的发现，我们的中心假设是KDM2A通过表观遗传抑制肿瘤抑制基因促进NSCLC 与KDM2A相关蛋白的合作。在拟议的研究中，我们试图了解 KDM2A使用分子机械研究，全基因组染色质测序接近和我们的新遗传小鼠模型。这里提出的基因工程鼠标模型将提供有关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 - 遗传机制，并将为开发以KDM2A为目标的疗法作为一种新的表观遗传治疗方法 NSCLC患者的大量子集。