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/?-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/?-catenin transcriptional function (Aim 1). The studies in this Aim will uncover a novel mechanism for the persistent activation of ?-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.
Glioblastomas (GBM) are the most common and fatal brain tumors. If the Specific Aims of this grant application are completed, we will understand a new mechanism of GBM tumorigenesis through abnormal cell growth and invasion of the tumor cells controlled by the integration of Wnt/?-catenin and KDM4C signaling pathways; and we will learn how to inhibit KDM4C expression in GBM. This information is highly relevant to the development of novel therapeutic agents that modulate enzymatic functions of KDM4C to control this deadly disease.
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