Epigenetic Modulation of Wnt/Beta-catenin Pathway and Tumorigenesis of Glioma Cells by KDM4C

 描述(申请人提供)：胶质瘤侵袭性强，侵袭性强，对化疗和放射治疗耐药。胶质母细胞瘤(GBM)是最恶性的胶质瘤，其患者的平均生存期约为一年，目前尚无有效的治疗方法。基底膜的高度侵袭性和增殖性使肿瘤复发且无法治愈。导致这种恶性行为的分子变化还知之甚少。这项建议的目的是获得关于GBM生长和侵袭的致病途径及其机制整合的明确知识，这对于开发有效的GBM患者的治疗方式至关重要。具体地说，这项建议中概述的研究将通过剖析肿瘤细胞固有的KDM4C(一种组蛋白去甲基酶)的功能，直接确定表观遗传学在IDH1野生型GBM发病中的作用。以往的研究表明，Wnt/β-catenin信号通路在癌细胞增殖、侵袭和肿瘤形成中起关键作用，但对该通路的表观遗传调控知之甚少。首先，我们建议研究KDM4C在增强Wnt/β-catenin转录功能中的作用和机制(目标1)。这一目标的研究将揭示β-连环蛋白介导的转录在基底膜中持续激活的新机制。其次，我们建议评估KDM4C表达在GBM细胞增殖、侵袭和致瘤性中的作用(目标2)。我们还将在动物模型中检验抑制KDM4C的治疗效果。第三，由于组蛋白去甲基酶领域还很年轻，人们对组蛋白去甲基酶的调控机制知之甚少。KDM4C在包括基底膜在内的大多数人类肿瘤中普遍过表达，但其过度表达的分子机制尚不清楚。因此，我们建议研究在GBM中KDM4C表达失调的分子机制(目标3)。如果这些特定目标的研究完成，我们不仅将了解这些主要途径的信号整合的新机制，而且我们还将了解表观遗传学调控对胶质瘤发生发展的生物学和临床影响。从长远来看，我们的研究可能会导致分子靶标的验证，这些靶标可以用于设计有效的策略，在临床上控制这种致命的疾病。因此，我们的研究结果将有助于更好地了解胶质瘤发生发展的分子机制，并有助于识别潜在的靶点，为恶性胶质瘤的治疗提供新的策略。

 DESCRIPTION (provided by applicant): Gliomas are aggressive, highly invasive, and resistant to chemotherapy and radiotherapy. The mean survival duration of patients with glioblastoma (GBM), the most malignant form of glioma, is approximately one year and there is no effective therapy to date. The highly invasive and proliferative nature of GBM renders the tumor relapse and incurable. The molecular changes leading to this malignant behavior are poorly understood. The goal of this proposal is to gain definitive knowledge on the causative pathways and their mechanistic integration underlying GBM growth and invasion, which are critical for developing effective therapeutic modalities for GBM patients. Specifically, the studie outlined in this proposal will directly determine the role of epigenetics in IDH1 wild-type GBM pathogenesis by dissecting the functions of tumor cell-intrinsic KDM4C, a histone demethylase. Previous studies have shown that Wnt/β-catenin signaling is critical for cancer cell proliferation invasion and cancer formation, whereas little is known about the epigenetic regulation of this pathway. First, we propose to investigate the role and mechanisms of KDM4C in enhancing Wnt/β-catenin transcriptional function (Aim 1). The studies in this Aim will uncover a novel mechanism for the persistent activation of β-catenin-mediated transcription in GBMs. Second, we propose to evaluate the function of KDM4C expression on cell proliferation, invasion and tumorigenicity of GBM cells (Aim 2). We will also examine the therapeutic effect of inhibition of KDM4C in an animal model. Third, as the field of histone demethylase is still young, relatively little is known about the mechanisms that regulate histone demethylase. KDM4C is commonly overexpressed in most human tumors, including GBM, while the molecular mechanisms for its overexpression remain unknown. Therefore, we propose to investigate the molecular mechanisms underlying the dysregulated KDM4C expression in GBM (Aim 3). If the studies of those specific aims are completed, not only will we understand new mechanisms for the signaling integration of those major pathways, but also we will learn the biological and clinical impacts of the epigenetics regulation on glioma development and progression. In the long term, our study may lead to the validation of molecular targets that can be used in designing effective strategies to control this deadly disease in clinics. Therefore, the findings from our proposed studies will contribute to a better understanding of the molecular mechanisms of glioma development and progression and help identify potential targets for novel therapeutic strategies against malignant glioma.