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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.

靶向KLF4和PRMT5在癌变中的相互作用