Menin-mediated epigenetic tumor suppression

描述(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发生肿瘤，它是由编码肿瘤抑制因子薄荷素的MEN1基因突变引起的。由于MEN1基因在约40%的散发性神经内分泌肿瘤患者中也发生了突变，了解脑膜素如何抑制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综合征的靶向治疗是缺乏的，但非常可取。去除MEN1基因的小鼠模型与MEN1肿瘤综合征的表型相似，是研究人类脑膜的肿瘤抑制功能的可靠模型。Menin是一种具有多种功能的支架蛋白，包括调节基因转录。其中一位是梅宁 作用是增加抗增殖细胞周期蛋白依赖性激酶抑制物(CDKI)、p18和p27的表达。然而，关于薄荷素是否或如何抑制促增殖基因的表达，人们知之甚少。我们最近的研究解决了Menin与转录因子Jund结合的共晶结构，并表明Menin通过抑制Jund的磷酸化和转录活性来抑制Jund的功能。此外，在小鼠的胰岛中，急性MEN1切除诱导了多个促增殖基因的表达，以及促进增殖的Hedgehog(HH)信号通路的组成部分。此外，我们发现脑膜素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，抑制促增殖基因的表达，以及促进Hedgehog信号的基因的表达，并且药物抑制HH信号对MEN1肿瘤有效。为了验证这些假说，目的1将研究脑膜素如何通过调节JUND和精氨酸甲基转移酶，以及它与神经内分泌肿瘤细胞中由脑膜素调节的CDKI轴的相互作用，在表观遗传学上控制细胞周期蛋白D1的表达。目的2，利用条件性基因敲除小鼠模型，确定精氨酸甲基转移酶在调控基因表达、Hedgehog信号转导和β细胞增殖中的作用。目的3将利用小鼠MEN1模型，通过靶向HH信号和CDK轴来评估实验性治疗对MEN1肿瘤的影响。总而言之，这些研究可能会揭开一种新的范式，以了解薄荷素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信号和CDK抑制剂，我们拟议的研究可能会加速基础和机制研究向使用HH信号和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转变。

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.