Role of the Histone Modifier KDM2A in Lung Cancer

项目总结 肺癌是美国和世界范围内癌症死亡的主要原因。非小细胞肺癌 (非小细胞肺癌)占所有肺癌病例的85%。非小细胞肺癌的五年生存率(16%) 患者是所有恶性肿瘤中最低的之一，在过去的三年中没有明显的改善 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物动态控制的，即组蛋白 赖氨酸甲基转移酶(甲基化写入者)和去甲基酶(甲基化擦除者)。与伟大的 我们对激酶信号通路、组蛋白甲基化的致病作用的了解进展 非小细胞肺癌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物的过程中 对于非小细胞肺癌的致癌作用，我们最近发现在非小细胞肺癌肿瘤中，组蛋白H3赖氨酸36(H3K36) 去甲基酶KDM2A(也称为FBXL11和JHDM1A)经常过度表达。我们的结果显示 KDM2A基因敲除对高表达KDM2A的NSCLC细胞的致瘤和转移能力的强烈抑制 小鼠异种移植模型及KDM2A过表达促进肿瘤细胞增殖和侵袭的研究 KDM2a-低非小细胞肺癌细胞。长期目标是确定组蛋白修饰物KDM2a在肺中的作用 致瘤性。我们的其他结果显示，KDM2A抑制了肿瘤抑制基因，如 双特异性磷酸酶3(DUSP3)。他们还表明，KDM2A增强了ERK1/2信号的重要性 通过表观遗传下调ERK1/2磷酸酶DUSP3，促进细胞增殖和侵袭。高 在两个不同的NSCLC患者队列中，KDM2a水平与预后不良相关，表明 KDM2A是一种新的预后不良的表观遗传学标记。根据这些确凿的发现，我们的中央 假说认为KDM2A通过表观遗传学途径抑制肿瘤抑制基因促进非小细胞肺癌 与KDM2A型相关蛋白合作(S)。在拟议的研究中，我们试图了解 KDM2A在肺肿瘤发生中的分子机制研究和全基因组染色质测序 方法，以及我们新的遗传小鼠模型。这里提出的转基因小鼠模型将 提供关于KDM2A如何促进非小细胞肺癌的体内洞察力。此外，我们的研究有望发现新的 癌症-KDM2A促进肺癌的表观遗传机制，并将为 KDM2A靶向疗法的发展作为一种新的表观遗传学治疗方法 相当一部分非小细胞肺癌患者。

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.