Regulation of tumor suppression by alpha-ketoglutarate

项目摘要 许多常见的癌基因和肿瘤抑制因子直接调节支持癌症的代谢途径 细胞存活、生长和增殖。代谢酶还有助于调节染色质景观： 多种细胞代谢物作为酶的关键共底物，所述酶存款或去除化学物质 对组蛋白和DNA的修饰。几种代谢酶的致癌突变导致 干扰组蛋白和DNA正常维持的代谢物的病理性蓄积 修改.然而，如果没有这些特定的代谢突变，是否更普遍的癌症- 由常见癌基因和肿瘤抑制基因驱动的相关代谢改变同样影响 染色质景观的调节仍然知之甚少。使用胰腺癌的小鼠模型 由于肿瘤抑制基因p53的可逆表达，我们发现p53控制着肿瘤细胞的水平， 细胞内α-酮戊二酸（αKG），α KG依赖性双加氧酶家族的一种专性共底物 包括DNA甲基胞嘧啶氧化酶的10 - 11（泰特）家族。在恶性肿瘤中恢复p53功能 胰腺癌细胞触发了细胞内αKG的积累，这是必要的，也是足够的， 增加泰特活性标志物，诱导肿瘤细胞分化和抑制肿瘤进展。 我们的研究结果提出了p53介导的αKG积累和伴随的α KG表达的变化可能性。 染色质景观和基因表达谱有助于野生型的肿瘤抑制功能 第53页。这项工作的目标是确定野生型p53如何发挥作用，以调节细胞αKG水平， 对致癌应激的反应以及αKG如何促进p53介导的肿瘤抑制。我们假设 p53对代谢途径的调节促进了αKG的积累，从而激活了基因 表达程序，防止恶性进展。为了解决这个问题，我们将 确定p53调节αKG的机制（目的1）;阐明αKG 诱导肿瘤分化（目的2），并测试αKG是否是恶性进展的屏障（目的3）。的 拟议中的实验将揭示人类肿瘤中常见的代谢改变如何影响肿瘤的生长。 以维持恶性状态，并确定可以靶向增强肿瘤细胞增殖的途径。 甚至在恶性细胞中抑制输出。

PROJECT SUMMARY Many common oncogenes and tumor suppressors directly regulate metabolic pathways that support cancer cell survival, growth and proliferation. Metabolites also contribute to the regulation of the chromatin landscape: multiple cellular metabolites serve as critical co-substrates of enzymes that deposit or remove chemical modifications on histones and DNA. Oncogenic mutations in several metabolic enzymes result in the pathological accumulation of metabolites that interfere with normal maintenance of histone and DNA modifications. However, absent these specific metabolic mutations, whether the more general cancer- associated metabolic alterations driven by common oncogenes and tumor suppressors likewise affect the regulation of the chromatin landscape remains poorly understood. Using mouse models of pancreatic cancer harboring reversible expression of the tumor suppressor p53, we discovered that p53 controls levels of intracellular alpha-ketoglutarate (αKG), an obligate co-substrate of a family of αKG-dependent dioxygenases that includes the ten-eleven (TET) family of DNA methylcytosine oxidases. Restoring p53 function in malignant pancreatic cancer cells triggered intracellular αKG accumulation, which was both necessary and sufficient to increase markers of TET activity, induce tumor cell differentiation and blunt tumor progression. Our findings raise the possibility that p53-mediated accumulation of αKG and concomitant changes in the chromatin landscape and gene expression profiles contribute to the tumor suppressive function of wild-type p53. The goal of this work is to determine how wild-type p53 functions to regulate cellular αKG levels in response to oncogenic stress and how αKG contributes to p53-mediated tumor suppression. We hypothesize that regulation of metabolic pathways by p53 promotes accumulation of αKG, thereby activating gene expression programs that safeguard against malignant progression. To address this hypothesis, we will determine the mechanisms by which p53 regulates αKG (Aim 1); elucidate the pathways through which αKG induces tumor differentiation (Aim 2), and test whether αKG is a barrier to malignant progression (Aim 3). The proposed experiments will reveal how metabolic alterations that commonly occur in human tumors contribute to the maintenance of the malignant state and identify pathways that can be targeted to enforce tumor suppressive outputs even in malignant cells.