The role of PTEN feedback mechanism in cancer

项目摘要 PTEN(磷酸酶和张力蛋白同源物)是人类最常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两个方面。首先，虽然PTEN函数可以是 受遗传综合征和散发性癌症基因突变的影响，翻译后 PTEN的修饰(PTM)可能在PTEN功能的动态调节中起关键作用。先前的研究关于 PTEN PTMS，包括本奖项支持的我们的工作，发现解除管制的泛素化和 去泛素化会对PTEN的稳定性和亚细胞定位产生不利影响，从而导致 肿瘤发生学。其次，PTEN通过PI3K-AKT-mTOR发挥其多种肿瘤抑制作用 然而，PTEN的作用也被证明超出了PI3K的控制，与PTEN一起 与控制基因组稳定性和细胞周期进程有关，尽管机制尚不清楚。 这项应用的总体目标是研究核PTEN介导的肿瘤的机制 抑制，侧重于癌症特异性PTM对PTEN区划和非典范的调节 其功能不依赖于其胞浆磷酸酶活性。我们新的初步研究揭示了这部小说 肿瘤中核PTEN的上游PTM机制和必需的下游效应因子。多元组学 蛋白质组、转录组和表观基因组的分析表明，PTEN-染色质之间存在明显的联系 重塑因子轴和细胞核内基因组的完整性。此外，这种与PTEN相关的新型染色质 在缺乏核PTEN的癌细胞中，重塑因子赋予合成的重要性。基于这些 观察到，我们假设规范和非规范PTEN信号协同减少 肿瘤发生和治疗耐药。为了验证这一假设，我们将(1)确定PTEN PTM是如何发生的 以及它们在癌症中的作用；(2)确定PTEN在肿瘤发生和基因组不稳定中的非典型作用； (3)探讨PTEN-染色质重塑因子轴在肿瘤中的治疗潜力。完成 这个项目不仅将深入了解分子和细胞机制，新的 PTEN的特征性PTM打破了其规范和非规范信号之间的平衡，但也 提供有关精确治疗PTEN丢失的有效策略开发的关键信息。 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.