Regulation of tumor suppression by alpha-ketoglutarate

项目总结 许多常见的癌基因和抑癌基因直接调节支持癌症的代谢途径 细胞的存活、生长和增殖。代谢物也有助于染色质景观的调节： 多种细胞代谢物是储存或去除化学物质的酶的关键共底物。 组蛋白和DNA的修饰。几种代谢酶的致癌突变导致 代谢产物病理性堆积，干扰组蛋白和DNA的正常维持 修改。然而，如果没有这些特定的代谢突变，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变化同样会影响 对染色质景观的调控仍然知之甚少。用小鼠胰腺癌模型 通过可逆表达抑癌基因P53，我们发现P53控制着 细胞内α-酮戊二酸(αKG)，αKG依赖的双加氧酶家族的专性共底物 这包括十-十一(Tet)家族的DNA甲基胞嘧啶氧化酶。恶性肿瘤患者P53功能的恢复 胰腺癌细胞触发细胞内αKG积聚，这是必要的，也是充分的 增加Tet活性标志物，诱导肿瘤细胞分化，抑制肿瘤进展。 我们的发现增加了P53介导的αKG积聚和伴随的变化在 染色质景观和基因表达谱对野生型抑瘤作用的影响 P53。这项工作的目标是确定野生型p53如何调节细胞内αKG水平 对致癌压力的反应以及αKG如何在P53介导的肿瘤抑制中发挥作用。我们假设 P53对代谢途径的调节促进αKG的积聚，从而激活基因 防止恶性进展的表达程序。为了解决这一假设，我们将 确定P53调节αKG的机制(目标1)；阐明αKG 诱导肿瘤分化(目标2)，并测试αKG是否为恶性进展的障碍(目标3)。这个 拟议中的实验将揭示人类肿瘤中常见的代谢变化是如何起作用的。 以维持恶性状态，并确定可靶向实施肿瘤的途径 即使在恶性细胞中也有抑制作用。

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.