The role of PTEN feedback mechanism in cancer

项目摘要 PTEN（磷酸酶和张力蛋白同源物）是在肿瘤细胞中最常见的改变的肿瘤抑制基因之一。 人类癌症这个项目的首要前提是双重的。首先，虽然PTEN功能可以被 遗传综合征和散发性癌症中的基因突变，翻译后 PTEN的修饰（PTMs）可能在PTEN功能的动态调节中起关键作用。先前的研究 PTEN PTM，包括我们获得该奖项支持的工作，确定了去调节泛素化， 去泛素化导致对PTEN稳定性和亚细胞定位的有害影响，从而引起 肿瘤发生其次，PTEN通过PI 3 K-AKT-mTOR实现其许多肿瘤抑制作用。 然而，PTEN的作用也已被证明超出了PI 3 K的控制， 参与控制基因组稳定性和细胞周期进程，尽管机制尚不清楚。 本申请的总体目标是研究核PTEN介导的肿瘤的机制， 抑制，重点是癌症特异性PTM调节PTEN区室化和非规范 其功能独立于其细胞质磷酸酶活性。我们新的初步研究揭示了 上游PTM机制和必要的下游效应细胞核PTEN在癌症中。多组学 蛋白质组、转录组和表观基因组的分析揭示了PTEN-染色质 重塑因子轴和细胞核内的基因组完整性。此外，这种新的PTEN相关染色质 重塑因子赋予缺乏核PTEN的癌细胞合成必需性。基于这些 根据观察，我们假设典型和非典型的PTEN信号传导协调地减少了 肿瘤发生和治疗抗性。为了验证这一假设，我们将（1）确定PTEN PTM如何发生 （2）明确PTEN在肿瘤发生和基因组不稳定性中的非经典作用; (3)探索PTEN-染色质重塑因子轴在癌症中的治疗潜力。完成 该项目不仅将深入了解新的生物学行为的分子和细胞机制， 表征的PTEN的PTM在其规范和非规范信号传导之间倾斜平衡，而且 产生关于精确治疗PTEN缺失的有效策略的发展的关键信息。 功能驱动的癌症

Project Summary PTEN (phosphatase and tensin homolog) is among the most commonly altered tumor suppressor genes in human cancers. The overarching premise of this project is twofold. First, while PTEN function can be compromised by genetic mutations in inherited syndromes and sporadic cancers, post-translational modifications (PTMs) of PTEN may play key roles in the dynamic regulation of PTEN function. Prior studies on PTEN PTMs, including our work supported by this award, identified that deregulated ubiquitination and deubiquitination lead to detrimental effects on PTEN stability and subcellular localization, thereby causing tumorigenesis. Secondly, PTEN fulfils many of its tumor suppressive roles through the PI3K-AKT-mTOR pathway; however, the role of PTEN has also been shown to extend beyond the control of PI3K, with PTEN implicated in controlling genomic stability and cell cycle progression, although the mechanism remains unclear. The overall goal of this application is to investigate the mechanisms of nuclear PTEN-mediated tumor suppression, focusing on cancer-specific PTM regulation of PTEN compartmentalization and non-canonical functions independent of its cytoplasmic phosphatase activity. Our new preliminary study revealed the novel upstream PTM mechanism and essential downstream effectors for nuclear PTEN in cancer. Multi-omics analyses of proteome, transcriptome and epigenome revealed a clear link between the PTEN-chromatin remodeling factor axis and genomic integrity within the nucleus. Further, this novel PTEN-associated chromatin remodeling factor conferred synthetic essentiality in cancer cells lacking nuclear PTEN. Based on these observations, we hypothesize that canonical and non-canonical PTEN signaling coordinately reduces tumorigenesis and therapy resistance. To test this hypothesis, we will (1) determine how PTEN PTMs occur and their role in cancer; (2) define the non-canonical roles of PTEN in tumorigenesis and genomic instability; (3) explore the therapeutic potential of the PTEN-chromatin remodeling factor axis in cancer. The completion of this project will not only gain insight into the molecular and cellular mechanisms by which the newly characterized PTM of PTEN tipping the balance between its canonical and non-canonical signaling, but also yield critical information about the development of effective strategies for precision treatment of PTEN loss-of- function driven cancers.