Targeting integrated metabolic and epigenetic pathways in childhood ependymomas

儿童室管膜瘤主要发生在后脑/后颅窝(PF)，发病率高， 死亡率。尽管进行了数十年的临床试验，但主要的治疗方法仍然是手术和辅助放射治疗， 是无法治愈的。PF室管膜瘤是独一无二的，因为超过80%的肿瘤没有复发的遗传 改装。相反，它们是表观遗传驱动的。它们被归类为A组(PFAs)肿瘤，定义如下 抑制标记H3K27me3和B组肿瘤的全球减少的表观遗传状态 没有显示H3K27me3的减少。PFAS主要发生在婴幼儿中，表现出一种令人沮丧的 预后较差，而PFB肿瘤主要见于青少年和成人，预后良好。 PFA中H3K27me3的减少是由一种名为EZHIP(EZH抑制蛋白)的蛋白介导的，该蛋白抑制 H3K27甲基转移酶EZH2的功能。然而，EZHIP如何推动PFAs的发病 仍然不为人知。癌症的一个主要特征是癌基因对细胞新陈代谢的重新编程，这 使肿瘤对葡萄糖等营养物质的吸收和新陈代谢增加。此外，新陈代谢和 表观遗传途径是紧密相连的，代谢物可以直接影响表观遗传修饰。为 例如，代谢物α-酮戊二酸(αKG)是H3K27组蛋白赖氨酸去甲基酶的关键辅因子 (KDM)，可以推动全球H3K27me3的减排。我们的初步数据显示，EZHIP增强了 糖酵解和三氯乙酸循环以产生高水平的αKG。我们的主要假设是EZHIP在表观遗传学上 重新连接细胞代谢以增加维持低H3K27me3水平所需的αKG产量。 因此，抑制这种表观遗传/代谢途径将具有治疗作用。两个具体目标将 支持我们的假设：目的1.阐明EZHIP促进糖酵解和 TCA循环代谢。目标2.确定靶向综合代谢/治疗的潜力 表观遗传途径来对抗这些肿瘤。这两个目标的结合将解决以下方面的重大差距 我们对PFA的了解，并为开发有效的治疗方法奠定了基础。

Ependymomas in children mainly arise in the hindbrain/ posterior fossa (PF) and carry high morbidity and mortality. Despite decades of clinical trials, mainstay treatment still remains surgery and adjuvant radiation, that are not curative. PF ependymomas are unique as more than 80% of tumors do not bear recurrent genetic alterations. Instead, they are epigenetically driven. They are classified into group-A (PFAs) tumors defined by an epigenetic state of global reduction of the repressive mark H3K27me3 and group-B (PFBs) tumors that do not show a reduction in H3K27me3. PFAs mainly occur in infants and young children and exhibit a dismal prognosis, while PFB tumors are mainly observed in adolescents and adults and bear an excellent prognosis. Reduced H3K27me3 in PFAs is mediated by a protein termed EZHIP (EZH inhibitory protein) that suppresses the function of the H3K27 methyltransferase EZH2. However, how EZHIP drives the pathogenesis of PFAs remains unknown. A central hallmark of cancer is reprograming of cellular metabolism by oncogenes, which enables increased uptake and metabolism of nutrients such as glucose by tumors. Moreover, Metabolic and epigenetic pathways are intimately linked and metabolites can directly impact epigenetic modifications. For example, the metabolite α-ketoglutarate (αKG) is a critical cofactor for the H3K27 histone lysine demethylases (KDMs) that can drive global reduction of H3K27me3. Our preliminary data show that EZHIP enhances glycolysis and TCA cycle to produce high αKG levels. Our overarching hypothesis is that EZHIP epigenetically rewires cellular metabolism to increase αKG production that is required to maintain low H3K27me3 levels. Consequently, suppressing this epigenetic/ metabolic pathway will be therapeutic. Two specific aims will address our hypothesis: Aim 1. Elucidate the molecular mechanisms by which EZHIP enhances glycolysis and TCA cycle metabolism. Aim 2. Determine the therapeutic potential of targeting an integrated metabolic/ epigenetic pathway to combat these tumors. The combination of these two aims will address significant gaps in our understanding of PFAs and lay the groundwork to develop effective treatments.