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Genetic Validation of the Protein Arginine Methyltransferase PRMT5 as a Candidate Therapeutic Target in Glioblastoma
Open accessPublished version of a preprint
Abstract
Glioblastoma is the most common and aggressive histologic subtype of brain cancer with poor outcomes and limited treatment options. Here, we report the selective overexpression of the protein arginine methyltransferase PRMT5 as a novel candidate theranostic target in this disease. PRMT5 silences the transcription of regulatory genes by catalyzing symmetric dimethylation of arginine residues on histone tails. PRMT5 overexpression in patient-derived primary tumors and cell lines correlated with cell line growth rate and inversely with overall patient survival. Genetic attenuation of PRMT5 led to cell-cycle arrest, apoptosis, and loss of cell migratory activity. Cell death was p53-independent but caspase-dependent and enhanced with temozolomide, a chemotherapeutic agent used as a present standard of care. Global gene profiling and chromatin immunoprecipitation identified the tumor suppressor ST7 as a key gene silenced by PRMT5. Diminished ST7 expression was associated with reduced patient survival. PRMT5 attenuation limited PRMT5 recruitment to the ST7 promoter, led to restored expression of ST7 and cell growth inhibition. Finally, PRMT5 attenuation enhanced glioblastoma cell survival in a mouse xenograft model of aggressive glioblastoma. Together, our findings defined PRMT5 as a candidate prognostic factor and therapeutic target in glioblastoma, offering a preclinical justification for targeting PRMT5-driven oncogenic pathways in this deadly disease. Cancer Res; 74(6); 1752–65. ©2014 AACR.
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“Similar to the context-dependent function of histone methyltransferases, the dynamic association of lysine demethylases with multi-protein complexes governs their stability and substrate specificity 180 .”
From The roles of DNA, RNA and histone methylation in ageing and cancer (2019) · cites this paper as [180]
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Metadata
- Authors
- Yan, F., Alinari, L., Lustberg, M. E., Katherine Martin, L., Cordero-Nieves, H. M., Banasavadi-Siddegowda, Y., Virk, S., Barnholtz-Sloan, J., Bell, E. H., Wojton, J., Jacob, N. K., Chakravarti, A., Nowicki, M. O., Wu, X., Lapalombella, R., Datta, J., Yu, B., Gordon, K., Haseley, A., Patton, J. T., Smith, P. L., Ryu, J., Zhang, X., Mo, X., Marcucci, G., Nuovo, G., Kwon, C.-H., Byrd, J. C., Chiocca, E. A., Li, C., Sif, S., Jacob, S., Lawler, S., Kaur, B., & Baiocchi, R. A.
- Affiliations
- Case Comprehensive Cancer Center (US)
- Authors' Affiliations: 1Division of Hematology, Department of Internal Medicine; 2Division of Infectious Diseases, Department of Internal Medicine; Departments of 3Neurosurgery; 4Molecular and Cellular Biochemistry; 5Chemical Engineering; 6Statistics; 7Pathology; 8Radiation Oncology; and 9College of Pharmacy, The Ohio State University (OSU), Columbus; 10Case Comprehensive Cancer Center; and 11Department of Epidemiology and Biostatistics, CWRU School of Medicine, Cleveland, Ohio
- Brigham and Women's Hospital (US)
- Corresponding author
- Kaur, Balveen
- Baiocchi, Robert A.
- ORCID
- Venue
- Cancer Research
- Published
- 2014-03-13
- Volume
- 74
- Issue
- 6
- Pages
- 1752-1765
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- PMC
- PMC3959215
- OpenAlex
- W2109483913
- Cited by
- 180
- References
- 40
- Citations by year
- 2026: 8 · 2025: 14 · 2024: 16 · 2023: 26 · 2022: 12 · 2021: 18 · 2020: 10 · 2019: 15 · 2018: 17 · 2017: 12 · 2016: 13 · 2015: 15 · 2014: 3
- FWCI
- 6.15
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (TL1TR000091)
- National Cancer Institute (R01CA150153, P30CA016058, P01CA163205)
- National Institute of General Medical Sciences (T32GM136583)
- National Institute of Neurological Disorders and Stroke (R01NS064607, R21NS071346)
- National Center for Advancing Translational Sciences
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cancer-related gene regulation
- Health Sciences › Medicine › Oncology › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA modifications and cancer
- Keywords
- PRMT5, protein arginine methyltransferase, glioblastoma, ST7, gene silencing, therapeutic target, prognostic factors, temozolomide, caspase-dependent apoptosis, cell migration, cell cycle arrest, patient survival, theranostic target
- MeSH terms
- Animals, Brain Neoplasms, Glioblastoma, Humans, Mice, Nude, Neoplasm Transplantation, Protein-Arginine N-Methyltransferases, Gene Expression, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Apoptosis, Mice, Knockout, Tumor Suppressor Proteins, RNA, Small Interfering, Cell Line, Tumor, Cell Proliferation, Mice, Kaplan-Meier Estimate, Gene Knockdown Techniques, Molecular Targeted Therapy
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