Menin-mediated epigenetic tumor suppression

描述（由申请人提供）：我们的长期目标是阐明遗传性多发性内分泌瘤1型（MEN1）综合征的分子机制，并为开发新的和改进的治疗方法铺平道路。MEN1综合征的特征是在几个内分泌器官中发生肿瘤，由MEN1基因突变引起，该基因编码肿瘤抑制因子menin。由于MEN1基因也在约40%的散发性神经内分泌肿瘤患者中发生突变，因此了解menin如何抑制MEN1肿瘤可能会为MEN1肿瘤和其他散发性内分泌肿瘤的发展提供新的见解。针对MEN1综合征的靶向治疗缺乏，但非常可取。Men1基因敲除小鼠模型与MEN1肿瘤综合征的表型相似，可作为研究人menin抑瘤作用的可靠模型。Menin是一种具有多种功能的支架蛋白，包括调节基因转录。梅宁的一个 作用是增加抗增殖细胞周期蛋白依赖性激酶抑制剂（CDKIs）、p18和p27的表达。然而，人们对menin是否或如何抑制促增殖基因的表达知之甚少。我们最近的研究解决了menin与转录因子JunD结合的共晶体结构，并表明menin通过抑制其磷酸化和转录活性来抑制JunD的功能。此外，急性Men1切除，在小鼠胰岛，诱导多个促增殖基因的表达，以及促增殖刺猬（Hh）信号通路的组件。此外，我们发现menin直接与转录抑制组蛋白精氨酸甲基转移酶相互作用， 抑制Hh信号相关基因。我们假设menin在功能上与JunD和甲基转移酶相互作用以抑制促增殖基因的表达，以及促进Hedgehog信号传导的基因，并且Hh信号传导的药理学抑制对于治疗MEN1肿瘤是有效的。为了验证这些假设，目的1将调查如何menin表观遗传控制细胞周期蛋白D1的表达，通过调节JunD和精氨酸甲基转移酶，其相互作用与menin调节的CDKI轴在神经内分泌肿瘤细胞。目的2，将确定精氨酸甲基转移酶在调节基因表达，刺猬信号，和β细胞增殖的条件敲除小鼠模型的作用。目的3将使用小鼠MEN1模型通过靶向Hh信号传导和CDK轴来评估实验疗法对MEN1肿瘤的影响。总的来说，这些研究将可能揭示一个新的范式，用于理解menin如何通过与关键转录因子、表观遗传调节因子和促增殖信号通路的串扰来抑制MEN1肿瘤综合征。由于已经开发出有效且临床安全的Hh信号传导和CDK抑制剂，我们提出的研究可能会加速将基础和机制研究转化为使用Hh信号传导和CDK抑制剂治疗MEN1肿瘤综合征和其他MEN1突变的神经内分泌肿瘤。

DESCRIPTION (provided by applicant): Our long-term goal is to elucidate the molecular mechanisms for inherited multiple endocrine neoplasia type 1 (MEN1) syndrome and pave the way to develop novel and improved therapy. MEN1 syndrome, characterized by the development of tumors in several endocrine organs, results from a mutation in the MEN1 gene, which encodes a tumor suppressor, menin. As the MEN1 gene is also mutated in ~40% of patients with sporadic neuroendocrine tumors, understanding how menin represses MEN1 tumors will likely provide new insights into how MEN1 tumors and other sporadic endocrine tumors develop. Targeted therapy against MEN1 syndrome is lacking yet highly desirable. Mouse models with ablation of the Men1 gene closely phenocopy MEN1 tumor syndrome, serving as reliable models for studying human menin's tumor suppressing function. Menin is a scaffold protein with multiple functions including regulation of gene transcription. One of menin's roles is to increase expression of anti-proliferative cyclin-dependent kinase inhibitors (CDKIs), p18 and p27. However, little is known as to whether or how menin represses expression of pro-proliferative genes. Our recent studies solved the co-crystal structure in which menin binds JunD, a transcription factor, with a deep pocket, and showed that menin inhibits JunD's function by suppressing its phosphorylation and transcriptional activity. Moreover, acute Men1 excision, in the islets of mice, induced expression of multiple pro-proliferative genes, as well as components of the pro-proliferative Hedgehog (Hh) signaling pathway. Further, we uncovered that menin directly interacts with a transcription-repressing histone arginine methyltransferase in suppressing Hh signaling-related genes. We hypothesize that menin functionally interacts with JunD and the methyltransferase to repress expression of pro-proliferative genes, as well as the genes that promote Hedgehog signaling, and that pharmacological suppression of Hh signaling is effective for treating MEN1 tumors. To test these hypotheses Aim 1 will investigate how menin epigenetically controls expression of cyclin D1 via regulating JunD and the arginine methyltransferase, and its interplay with the menin-regulated CDKI axis in neuroendocrine tumor cells. Aim 2, will determine the role of the arginine methyltransferase in regulating gene expression, Hedgehog signaling, and beta cell proliferation using conditional knockout mouse models. Aim 3 will evaluate the impact of experimental therapy on MEN1 tumors by targeting Hh signaling and the CDK axis using mouse MEN1 models. Collectively, these studies will likely unravel a new paradigm for understanding how menin suppresses MEN1 tumor syndrome via crosstalk with a key transcription factor, an epigenetic regulator, and a pro-proliferative signalig pathway. As effective and clinically safe Hh signaling and CDK inhibitors have already been developed, our proposed studies will likely accelerate translation of the basic and mechanistic studies to treating MEN1 tumor syndrome and other MEN1-mutated neuroendocrine tumors with the Hh signaling and CDK inhibitors.