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肿瘤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综合征的特点是在几个内分泌器官中发生肿瘤，是由编码肿瘤抑制因子menin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突变，了解menin如何抑制MEN1肿瘤可能为MEN1肿瘤和其他散发性内分泌肿瘤的发展提供新的见解。目前缺乏针对MEN1综合征的靶向治疗，但这是非常可取的。切除Men1基因的小鼠模型与Men1肿瘤综合征密切相关，为研究人类menin的抑瘤功能提供了可靠的模型。Menin是一种具有多种功能的支架蛋白，包括调控基因转录。menin的一个

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.