Role of the Histone Modifier KDM2A in Lung Cancer

项目摘要 肺癌是美国和全世界癌症死亡的主要原因。非小细胞肺癌 非小细胞肺癌（NSCLC）占所有肺癌病例的85%。NSCLC的5年生存率（16%） 患者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。 基因表达这种修饰受组蛋白甲基化修饰剂的动态控制，即，组蛋白 赖氨酸甲基转移酶（甲基化写入器）和脱甲基酶（甲基化清除器）。相比之下， 我们对激酶信号通路的理解的进展，组蛋白甲基化的致病作用， NSCLC中的修饰物在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， 我们最近发现，在NSCLC肿瘤中，组蛋白H3赖氨酸36（H3 K36） 脱甲基酶KDM 2A（也称为FBXL 11和JHDM 1A）经常过表达。我们的结果显示 KDM 2A敲低强烈抑制KDM 2A高表达NSCLC细胞的致瘤和转移能力， KDM 2A的过表达促进了小鼠异种移植瘤的增殖和侵袭， KDM 2A-低NSCLC细胞。长期目标是确定组蛋白修饰剂KDM 2A在肺组织中的作用。 致瘤性我们的额外结果显示，KDM 2A抑制肿瘤抑制基因，如： 双特异性磷酸酶3（DUSP 3）。它们还表明KDM 2A增强ERK 1/2信号传导， 通过表观遗传学下调ERK 1/2磷酸酶DUSP 3来促进细胞增殖和侵袭。高 在两个不同的NSCLC患者队列中，KDM 2A水平与不良预后相关，表明 KDM 2A是一种新的不良预后表观遗传标记。根据这些明确的发现，我们的中央 假设KDM 2A通过表观遗传学抑制肿瘤抑制基因促进NSCLC， 与KDM 2A相关蛋白的协同作用。在拟议的研究中，我们试图了解 KDM 2A在肺致瘤性中的分子机制研究，全基因组染色质测序 方法和我们新的遗传小鼠模型。这里提出的基因工程小鼠模型将 提供KDM 2A如何促进NSCLC的体内见解。此外，我们的研究有望揭示新的 癌症表观遗传机制，KDM 2A促进肺癌，并将提供一个基本原理， 开发KDM 2A靶向治疗作为治疗糖尿病的新的表观遗传治疗方法， NSCLC患者的重要子集。

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.