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Targeting interplay between KLF4 and PRMT5 in carcinogenesis

靶向 KLF4 和 PRMT5 在致癌作用中的相互作用

基本信息

批准号：
9977693
负责人：
Yong Wan
金额：
$ 25.32万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-08 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9977693
关键词：
Affect Apoptosis Arginine Breast Cancer Cell Breast Cancer Treatment Breast Cancer therapy Breast Carcinogenesis Cell division Cells Chemicals Chemosensitization DNA Damage DNA damage checkpoint Data Development Enzymes Exhibits GKLF protein Genetic Transcription Goals Human Impairment Lead Malignant - descriptor Mammary Neoplasms Mammary Tumorigenesis Mediating Methylation Methyltransferase Modeling Molecular Oncogenic Pathologic Patients Pharmaceutical Preparations Play Post-Translational Protein Processing Protein Methylation Proteins Radiation therapy Radiosensitization Regulation Role Testing The Cancer Genome Atlas Therapeutic Therapeutic Intervention Tumor Cell Invasion Xenograft procedure base cancer stem cell carcinogenesis clinically relevant genome integrity in vivo inhibitor/antagonist malignant breast neoplasm mouse model novel novel strategies protein complex self-renewal triple-negative invasive breast carcinoma tumor initiation tumor progression tumorigenesis ubiquitin-protein ligase

项目摘要

Targeting the interplay between KLF4 and PRMT5 in carcinogenesis The goal of this project is to determine the impact of interplay between KLF4 and PRMT5 in breast carcinogenesis and anti-breast cancer therapy. Krüppel-like factor 4 (KLF4) is a critical regulator of cell fate for cell division, apoptosis, and DNA damage, and plays an ambivalent role in tumorigenesis. Over 70% of human primary mammary cancers exhibit cellular accumulation of KLF4, and the impact of KLF4 on breast cancer formation has been recently indicated by the TCGA (The Cancer Genome Atlas). The most recent studies by us and others have demonstrated an oncogenic role for KLF4 in breast carcinogenesis. Nevertheless, how KLF4 is regulated and how its deregulation contributes to breast carcinogenesis remains unknown. Results from our recent purification of the KLF4 protein complex revealed that two critical enzymes, VHL and PRMT5, tightly interact with and regulate KLF4. While the ubiquitin E3 ligase VHL/VBC catalyzes KLF4 for ubiquitylation followed by degradation, we observed that methylation of KLF4 protein by PRMT5 (an arginine-based methyltransferase) results in the stabilization of KLF4 and promotion of KLF4-mediated transcription. Unexpected elevation of KLF4 levels due to enhanced KLF4 methylation counteracts KLF4 ubiquitylation, which in turn triggers tumor initiation and promotes tumor invasion. We further observed that deregulation of KLF4 methylation by aberrant PRMT5 expression impairs DNA damage checkpoint function, which could induce malignant transformation due to loss of genomic integrity. Thus, we ask if PRMT5 is a critical factor that determines the oncogenic role for KLF4 in breast carcinogenesis, and if the PRMT5-KLF4 cascade could be a novel target for breast cancer therapy. This proposal aims to determine the pathophysiological role of KLF4 methylation by PRMT5 in mammary tumorigenesis, and to further identify the clinical relevance of the KLF4-PRMT5 axis in breast cancer therapy. In this project, we plan to test the hypothesis that deregulation of KLF4 by PRMT5 promotes tumorigenesis and tumor invasion by pursuing the following specific aims: (1) to determine how methylation of KLF4 by PRMT5 regulates KLF4 protein stability and function; (2) to determine how the dysregulation of KLF4 by PRMT5 affects the self-renewal of breast cancer stem cells and promotes tumorigenesis; and (3) to determine the impact of deregulation of KLF4 by PRMT5 in breast tumor progression/invasion and validate the therapeutic intervention of our newly developed KLF4 methylation inhibitor in breast cancer treatment using murine models.

针对 KLF4 和 PRMT5 在致癌过程中的相互作用该项目的目标是确定 KLF4 和 PRMT5 之间相互作用对乳房的影响致癌作用和抗乳腺癌治疗。 Krüppel 样因子 4 (KLF4) 是细胞的关键调节因子细胞分裂、凋亡和 DNA 损伤的命运，并在肿瘤发生中发挥着矛盾的作用。超过 70% 的人类原发性乳腺癌表现出 KLF4 的细胞积累，其影响 TCGA（癌症基因组）最近表明 KLF4 对乳腺癌形成的影响阿特拉斯）。我们和其他人的最新研究表明 KLF4 在以下方面具有致癌作用：乳腺癌发生。尽管如此，KLF4 是如何受到监管的以及其放松管制如何有助于乳腺癌的发生机制仍不清楚。我们最近纯化 KLF4 蛋白的结果复合物揭示了两种关键酶 VHL 和 PRMT5 与 KLF4 紧密相互作用并对其进行调节。虽然泛素 E3 连接酶 VHL/VBC 催化 KLF4 进行泛素化，然后降解，但我们观察到 PRMT5（一种基于精氨酸的甲基转移酶）对 KLF4 蛋白的甲基化导致 KLF4 的稳定和 KLF4 介导的转录的促进。 KLF4 意外升高由于 KLF4 甲基化增强而导致的水平升高抵消了 KLF4 泛素化，进而引发肿瘤启动并促进肿瘤侵袭。我们进一步观察到 KLF4 甲基化的失调 PRMT5 的异常表达会损害 DNA 损伤检查点功能，从而可能诱发恶性肿瘤由于基因组完整性丧失而导致的转化。因此，我们问 PRMT5 是否是一个关键因素确定 KLF4 在乳腺癌发生中的致癌作用，如果 PRMT5-KLF4 级联可能成为乳腺癌治疗的新靶点。该提案旨在确定 PRMT5 对 KLF4 甲基化在乳腺肿瘤发生中的病理生理作用，并进一步确定 KLF4-PRMT5 轴在乳腺癌治疗中的临床相关性。在这个项目中，我们计划检验 PRMT5 对 KLF4 的失调促进肿瘤发生和肿瘤的假设通过追求以下具体目标来入侵：（1）确定PRMT5如何甲基化KLF4 调节 KLF4 蛋白的稳定性和功能； (2) 确定KLF4的失调是如何通过 PRMT5影响乳腺癌干细胞的自我更新，促进肿瘤发生； (3) 至确定 PRMT5 对 KLF4 的失调对乳腺肿瘤进展/侵袭的影响，以及验证我们新开发的 KLF4 甲基化抑制剂对乳腺的治疗干预作用使用小鼠模型进行癌症治疗。