Understanding the epigenetic basis of human familial paraganglioma

描述（由申请人提供）：了解人类家族性副神经节瘤的表观遗传基础。 我们的实验室对了解代谢缺陷如何促进肿瘤发生感兴趣。具体来说，我们研究家族性副神经节瘤（PGL），神经内分泌癌，作为一个模型，证实代谢紊乱。家族性PGL表现为常染色体显性遗传，是由于编码琥珀酸脱氢酶（SDH）（一种三羧酸（TCA）循环酶）亚基的基因的两个拷贝丢失所致。SDH功能的丧失特别有趣，因为它证实了有氧糖酵解的瓦尔堡效应，这是许多癌症的一个神秘特征。到目前为止，还没有明确的解释SDH功能的丧失如何导致神经内分泌细胞中的肿瘤形成。此外，没有临床前模型来研究这种癌症。该提案的长期目标是了解SDH功能丧失如何在神经内分泌细胞中诱导PGL。这些知识将为PGL的预防和治疗提供新的方法。我们的中心假设是琥珀酸积累引起的双加氧酶抑制引起致癌表观遗传效应，包括缺氧诱导因子（HIF）的激活、组蛋白甲基化的积累和5-羟甲基-脱氧胞嘧啶（5 hmdC）的耗竭。我们的策略是开发三种模型来研究琥珀酸积累。这些包括（1）人类家族性PGL肿瘤组织学标本，（2）SDHB慢病毒敲低人类组织培养细胞，和（3）小鼠SDHC-/-细胞系。目的1将检查SDH丢失在PGL肿瘤标本中的作用。目的2将确定组织培养细胞中SDH敲低的影响，以及这些影响是否可以通过SDH基因替换或增加2-酮戊二酸水平来克服。最后，目标3将表征小鼠SDHC-/-细胞系中SDH损失的影响。

DESCRIPTION (provided by applicant): Understanding the epigenetic basis of human familial paraganglioma. Our laboratory is interested in understanding how defects in metabolism can promote tumorigenesis. Specifically, we study familial paraganglioma (PGL), a neuroendocrine cancer, as a model that exemplifies metabolic derangement. Familial PGL displays autosomal dominant inheritance and is due to loss of both copies of genes encoding subunits of succinate dehydrogenase (SDH), a tricarboxylic acid (TCA) cycle enzyme. Loss of SDH function is particularly interesting because it exemplifies the Warburg effect of aerobic glycolysis, a mysterious feature of many cancers. To date, there is no clear explanation for how loss of SDH function leads to tumor formation in neuroendocrine cells. Furthermore, there is no preclinical model to study this cancer. The long-term goal of this proposal is to understand how loss of function of SDH induces PGL in neuroendocrine cells. This knowledge will provide new approaches to PGL prevention and treatment. Our central hypothesis is that dioxygenase inhibition by succinate accumulation causes oncogenic epigenetic effects including activation of Hypoxia Inducible Factor (HIF), accumulation of histone methylation, and depletion of 5-hydroxymethyl-deoxycytosine (5hmdC). Our strategy is to develop three models to study succinate accumulation. These include (1) human familial PGL tumor histology specimens, (2) SDHB lentiviral knockdown human tissue culture cells, and (3) a mouse SDHC-/- cell line. Aim 1 will examine the effects of SDH loss in PGL tumor specimens. Aim 2 will determine effects of SDH knockdown in tissue culture cells and if these effects can be overcome by SDH gene replacement or increasing 2-ketoglutarate levels. Finally, Aim 3 will characterize the effects of SDH loss in a mouse SDHC-/- cell line.