The role of PTEN feedback mechanism in cancer

PTEN反馈机制在癌症中的作用

• 批准号: 10658403
• 负责人: Min Sup Song
• 金额: $ 40.5万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658403
• 关键词: Adrenal Glands; Automobile Driving; Award; Biochemical; Cancer Patient; Cell Cycle; Cell Cycle Progression; Cell Nucleus; Cell Proliferation; Chromatin Remodeling Factor; Colorectal; Cytoplasm; DNA Repair; DNA Sequence Alteration; Data; Deubiquitination; Development; Ensure; Equilibrium; Essential Genes; Exclusion; FRAP1 gene; Feedback; Genome Stability; Genomic Instability; Genomics; Glutamates; Goals; Human; Impairment; In Vitro; Induction of Apoptosis; Inherited; Investigation; Knock-in Mouse; Knowledge; Lead; Link; Lysine; Malignant Neoplasms; Mass Spectrum Analysis; Mediating; Metabolic; Mission; Modeling; Modification; Molecular; Mutant Strains Mice; Mutate; Mutation; Nuclear; Nuclear Import; Organoids; PIK3CG gene; PTEN Hamartoma Tumor Syndrome; PTEN gene; Pathogenicity; Pathologic; Pathway interactions; Phosphoric Monoester Hydrolases; Physiological; Play; Post-Translational Protein Processing; Precision therapeutics; Prostatic hypertrophy; Protein Dephosphorylation; Proteome; Proto-Oncogene Proteins c-akt; Public Health; Regulation; Research; Resistance; Role; Signal Transduction; Succinates; Syndrome; Testing; Therapeutic; Tumor Suppression; Tumor Suppressor Genes; Ubiquitination; United States National Institutes of Health; Work; Zinc Fingers; cancer cell; cancer therapy; chromatin remodeling; epigenome; genome integrity; improved outcome; in vivo; insight; knock-down; loss of function; mouse model; multiple omics; mutant; novel; novel therapeutics; phosphoinositide-3,4,5-triphosphate; prevent; transcriptome; tumor; tumor growth; tumorigenesis

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.

项目概要 PTEN（磷酸酶和张力蛋白同源物）是最常见改变的肿瘤抑制基因之一 人类癌症。该项目的总体前提是双重的。首先，虽然PTEN功能可以 受到遗传综合征和散发性癌症、翻译后基因突变的损害 PTEN 的修饰（PTM）可能在 PTEN 功能的动态调节中发挥关键作用。先前的研究 PTEN PTM，包括我们受该奖项支持的工作，确定了放松管制的泛素化和 去泛素化会对 PTEN 稳定性和亚细胞定位产生不利影响，从而导致 肿瘤发生。其次，PTEN 通过 PI3K-AKT-mTOR 发挥其许多肿瘤抑制作用 途径；然而，PTEN 的作用也已被证明超出了 PI3K 的控制范围，PTEN 尽管其机制尚不清楚，但参与控制基因组稳定性和细胞周期进程。 本申请的总体目标是研究核PTEN介导的肿瘤的机制 抑制，重点关注 PTEN 区室化和非规范的癌症特异性 PTM 调节 其功能与其细胞质磷酸酶活性无关。我们新的初步研究揭示了小说 癌症中核 PTEN 的上游 PTM 机制和重要的下游效应子。多组学 蛋白质组、转录组和表观基因组的分析揭示了 PTEN-染色质之间的明确联系 重塑因子轴和细胞核内的基因组完整性。此外，这种新型 PTEN 相关染色质 重塑因子赋予缺乏核 PTEN 的癌细胞合成的必要性。基于这些 根据观察，我们假设规范和非规范 PTEN 信号传导协同减少 肿瘤发生和治疗耐药。为了检验这一假设，我们将 (1) 确定 PTEN PTM 是如何发生的 及其在癌症中的作用； (2) 定义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发现的分子和细胞机制 PTEN 的 PTM 特征决定了其规范和非规范信号传导之间的平衡，而且 产生有关制定有效策略来精确治疗 PTEN 缺失的关键信息 功能驱动的癌症。

项目成果

New Insights into the Role of E2s in the Pathogenesis of Diseases: Lessons Learned from UBE2O.

• DOI: 10.14348/molcells.2018.0008
• 发表时间: 2018-03-31
• 期刊: Molecules and cells
• 影响因子: 3.8
• 作者: Hormaechea-Agulla D;Kim Y;Song MS;Song SJ
• 通讯作者: Song SJ

A UBE2O-AMPKα2 Axis that Promotes Tumor Initiation and Progression Offers Opportunities for Therapy.

• DOI: 10.1016/j.ccell.2017.01.003
• 发表时间: 2017-02-13
• 期刊: Cancer cell
• 影响因子: 50.3
• 作者: Vila IK;Yao Y;Kim G;Xia W;Kim H;Kim SJ;Park MK;Hwang JP;González-Billalabeitia E;Hung MC;Song SJ;Song MS
• 通讯作者: Song MS