A novel small-molecule antagonizes PRMT5-mediated KLF4 methylation for targeted therapyResearch in context
Zhuan Zhou,
Zhiwei Feng,
Dong Hu,
Peng Yang,
Mert Gur,
Ivet Bahar,
Massimo Cristofanilli,
William J. Gradishar,
Xiang-qun Xie,
Yong Wan
Affiliations
Zhuan Zhou
Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States
Zhiwei Feng
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, United States
Dong Hu
Departments of Pathology and Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, United States
Peng Yang
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, United States
Mert Gur
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, United States
Ivet Bahar
Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, United States
Massimo Cristofanilli
Lynn Sage Breast Cancer Program, Department of Medicine-Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States
William J. Gradishar
Lynn Sage Breast Cancer Program, Department of Medicine-Hematology and Oncology, Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States
Xiang-qun Xie
Department of Pharmaceutical Sciences and Computational Chemical Genomics Screening Center, School of Pharmacy, University of Pittsburgh, United States; Correspondence to: X.-Q. Xie, Department of Pharmaceutical Sciences/Drug Discovery Institute, Computational Chemical Genomics Screening Center, School of Pharmacy and Center of Excellence for Computational Drug Abuse Research, 512-3 Salk Hall, School of Pharmacy, University of Pittsburgh, PA 15261, United States.
Yong Wan
Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine, United States; Department of Pharmacology, Northwestern University Feinberg School of Medicine, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, United States; Correspondence to: Y. Wan, Department of Obstetrics and Gynecology, Northwestern University Feinberg School of Medicine and Robert H. Lurie Comprehensive Cancer Center, 303 East Superior, Lurie Medical Research Center, Chicago, IL 60611, United States.
Background: Triple negative breast cancers (TNBCs) have a poor prognosis and are not amenable to endocrine- or HER2-targeted therapies. The malignant and invasive feature of TNBCs is correlated with its high cancer stem cell population. Recent results from us and others have unveiled an oncogenic role for the PRMT5-KLF4 axis in regulating tumor progression by orchestrating the stemness in mammary tumor cell as well as genome stability. Methylation of KLF4 by PRMT5 leads to KLF4 stabilization, resulting in promoting mitogenesis. Methods: We have developed a small molecule inhibitor, WX2–43, that specifically intercepts the interaction between PRMT5 and KLF4, thereby enhancing KLF4 degradation. Findings: Results from our characterization demonstrate that WX2–43 binds to the region between amino acids L400-M500 on PRMT5. Degradation of KLF4 down-regulates KLF4-mediated genes transcription. We have characterized the potent effect for WX2–43 in inhibiting PRMT5-KLF4 binding that, in turns, suppresses tumor progression and induces tumor cell death in both TNBC cultured-cell and animal models. Interpretation: WX2–43-mediated inhibition of KLF4 methylation by PRMT5 could be a potential strategy for anti-TNBC treatment. Fund: This work was supported, in whole or in part, by National Institutes of Health grants CA202963 and CA202948 (Wan), R21HL109654 (Xie), P30DA035778 (Xie and Bahar) and P41GM103712 (Bahar). Keywords: WX2-43, PRMT5, KLF4, Methylation and breast cancer
