Molecular Basis of Familial Paraganglioma

描述（由申请人提供）：癌细胞被比作超速行驶的汽车。突变的癌基因会抑制油门踏板；突变的肿瘤抑制基因破坏了刹车。虽然这种类比通常很有用，但在家族副神经节瘤（PGL）这个引人入胜的病例中完全失败了。令人惊讶的是，PGL是一种由中枢代谢三羧酸（TCA）循环中琥珀酸脱氢酶缺失引起的神经内分泌癌。这相当于严重破坏了汽车的引擎！代谢酶的功能丧失突变如何可能致癌？为什么只在神经内分泌细胞中发生？这些不可抗拒的生化问题推动了这一提议，其答案将对远远超出PGL的癌症治疗具有重要意义。核心假设是，由于SDH缺失导致的琥珀酸积累通过抑制至少三种不同的2-酮戊二酸依赖的双加氧酶（产生琥珀酸作为副产物）的表观遗传效应触发神经内分泌细胞转化。这就像一辆超速行驶的癌症汽车失去了控制，因为司机被故障发动机产生的烟雾所陶醉！我们假设双加氧酶抑制通过新的表观遗传效应改变基因表达，包括(i)缺氧诱导因子（HIF）的不适当激活，（ii）甲基化组蛋白的积累，以及（iii）基因组5-羟甲基胞嘧啶的消耗。策略是表征PGL肿瘤和缺乏SDH功能的哺乳动物细胞，并开发用于秀丽隐杆线虫药物筛选的PGL线虫模型。目的1将寻找双加氧酶抑制原发人PGL肿瘤样本的证据。目的2将探讨培养的缺乏SDH的人和小鼠细胞对双加氧酶的抑制作用。Aim 3将监测条件SDH破坏小鼠的PGL肿瘤发生情况。最后，Aim 4将开发秀丽隐杆线虫PGL模型，以发现新的治疗方法。

DESCRIPTION (provided by applicant): Cancer cells have been likened to speeding cars. Mutated oncogenes hold down accelerator pedals; mutated tumor suppressor genes ruin brakes. Though often helpful, this analogy completely fails in the fascinating case of familial paraganglioma (PGL). Amazingly, PGL is a neuroendocrine cancer caused by loss of succinate dehydrogenase in the tricarboxylic acid (TCA) cycle of central metabolism. This is equivalent to severely disabling the engine of a car! How can loss-of-function mutations in a metabolic enzyme possibly be oncogenic, and why only in neuroendocrine cells? These irresistible biochemical questions drive this proposal, and answers will have significance for cancer therapy far beyond PGL. The central hypothesis is that succinate accumulation due to loss of SDH triggers neuroendocrine cell transformation by epigenetic effects resulting from inhibition of at least three different 2-ketoglutarate- dependent dioxygenase enzymes that produce succinate as a byproduct. It is as if the speeding car of cancer loses control because the driver is intoxicated by fumes from a faulty engine! We hypothesize that dioxygenase inhibition alters gene expression by novel epigenetic effects including (i) inappropriate activation of Hypoxia Inducible Factor (HIF), (ii) accumulation of methylated histones, and (iii) depletion of genomic 5-hydroxymethylcytosine. The strategy is to characterize PGL tumors and mammalian cells lacking SDH function, and to develop a nematode model of PGL for drug screening in Caenorhabditis elegans. Aim 1 will seek evidence for dioxygenase inhibition in primary human PGL tumor samples. Aim 2 will explore dioxygenase inhibition in cultured human and mouse cells lacking SDH. Aim 3 will monitor PGL tumorigenesis in mice with conditional SDH disruption. Finally, Aim 4 will develop a C. elegans model of PGL to uncover new therapeutics.