Targeting PRMT5 to combat cancer drug resistance associated with neuroendocrine differentiation

项目总结 神经内分泌肿瘤(Net)发生于多个器官，有许多相似之处。虽然篮网是 与乳腺癌和肺癌相比，NETS的发病率正在稳步上升。传统型 治疗NETs的方法并不有效，NETs患者的存活率仍然很低。转接- 向Net的分化被认为是所有上皮性癌症耐药的一种机制， 因此，了解NETS的产生和发展是很重要的。然而，学习中的挑战 Net在开发治疗方面的进展有限。默克尔细胞癌(MCC)是一种高级别的 皮肤比黑色素瘤更致命，约80%的病例是由默克尔细胞多瘤病毒引起的。这种类型 因此，Net及其病毒致癌因素是研究Net生物学的一个有价值的模型。篮网 通常表现出较低的突变率，表观遗传修饰被认为是重要的驱动因素。在……里面 在这项建议中，我们将严格评估蛋白质精氨酸甲基转移酶5(PRMT5)在MCC中作为一种 通过研究PRMT5介导的精氨酸甲基化与MCC相关的表观遗传调节因子 神经内分泌分化。我们假设PRMT5介导组蛋白甲基化和下游 受这种甲基化影响的靶分子是维持MCC净状态所必需的，并且可以另外 影响癌症耐药性。本项目将(1)确定PRMT5对MCC和 耐药，以及(2)确定与MCC净状态相关的PRMT5靶点。PRMT5的抑制剂有 目前正在进行几种癌症的临床试验，并了解PRMT5的分子机制 作为MCC的表观遗传调节因子，将有助于评估PRMT5抑制剂作为潜在治疗药物的使用 不仅是对MCC的干预，也是对其他Net的治疗。

PROJECT SUMMARY Neuroendocrine Tumors (NETs) occur in multiple organs and share many similarities. Although NETs are relatively rare compared to breast and lung cancers, the incidence of NETs is steadily increasing. Conventional therapies are not effective in treating NETs, and the survival rates of patients with NETs remain low. Trans- differentiation to NETs is suggested as a mechanism of cancer therapy resistance across all epithelial cancers, therefore it is important to understand the initiation and progression of NETs. However, challenges in studying NETs have limited progress in developing therapies. Merkel cell carcinoma (MCC) is a high-grade NET of the skin that is more deadly than melanoma, with about 80% of cases caused by Merkel cell polyomavirus. This type of NET with its viral oncogenic causal factors is thus a valuable model to investigate the biology of NETs. NETs normally exhibit low mutation rates, and epigenetic modifications are hypothesized to be important drivers. In this proposal, we will critically evaluate the role of Protein Arginine Methyltransferase 5 (PRMT5) in MCC as an epigenetic regulator in MCC by investigating PRMT5-mediated arginine methylation that is associated with neuroendocrine differentiation. We hypothesize that PRMT5-mediated histone methylation and downstream targets affected by this methylation are required for the maintenance of NET state of MCC and can additionally affect cancer drug resistance. This project will (1) determine effects of PRMT5 on the NET identity of MCC and drug resistance, and (2) identify PRMT5 targets associated with the NET state of MCC. Inhibitors for PRMT5 are currently in clinical trials for several types of cancer, and understanding the molecular mechanisms of PRMT5 as an epigenetic regulator in MCC will help evaluate the use of PRMT5 inhibitors as a potential therapeutic intervention not only for MCC but also for the treatment of other NETs.