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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.

Glioblastoma Multiforme (GBM) is associated with a dismal prognosis despite intensive multimodal therapy, highlighting the need for novel therapeutic approaches. Chromatin remodeling complexes and associated co-repressors such as histone deacetylases (HDAC), DNA methyltransferases (DNMT) and protein arginine methyltransferase 5 (PRMT5) are involved in silencing tumor suppressor and regulatory gene expression and may contribute to glial cell transformation. PRMT5 silences the transcription of key regulatory genes by symmetric di-methylation (S2Me) of arginine (R) residues on histone proteins (H4R3 and H3R8) and works more efficiently when associated with other co-repressor enzymes. We have previously identified PRMT5 over-expression in GBM cell lines, primary GBM tumors, and GBM that spontaneously develop in a pre-clinical mouse model. The degree of PRMT5 over-expression inversely correlated with survival of GBM patients (r=-0.57, p=0.0001) and correlated with proliferation of GBM cell lines (r=0.81, p Citation Format: Fengting Yan, Kate Gordon, Kiran Mahasenan, Mark Lustberg, Lapo Alinari, Christian T. Earl, Balveen Kaur, Chenglong Li, Robert A. Baiocchi. Developing a first in class of drug to inhibit protein arginine methyltransferase 5 (PRMT5) enzyme dysregulation in glioblastoma multiforme. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4637. doi:10.1158/1538-7445.AM2013-4637

High grade astrocytomas are aggressive brain tumors that are associated with a dismal prognosis and are incurable with a median survival of less than 15 months despite intensive multimodal therapy. The linability to effectively target grade III and grade IV (glioblastoma multiforme, GBM) astrocytomas highlights the need for novel therapeutic approaches. Recent studies have shown that epigenetic regulation of chromatin plays a central role in the control of cell growth, differentiation, and survival. Chromatin remodeling enzymes like histone deacetylases, DNA methyltransferases and protein arginine methyltransferase 5 (PRMT5) are involved in silencing tumor suppressor gene (TSG) expression and may contribute towards cellular transformation. PRMT5 silences the transcription of key regulatory genes by symmetric di-methylation (S2Me) of arginine (R) residues on histone proteins (H4R3 and H3R8) and works more efficiently when associated with other co-repressor enzymes. Eight patient-derived GBM cell lines and 45 primary GBM tumors showed abundant expression of PRMT5 protein. Confocal microscopy and immunohistochemical staining showed the PRMT5 signal to localize primarily to the nucleus. Normal brain tissue, normal human astrocytes and low/intermediate grade astrocytomas failed to show PRMT5 expression. The degree of PRMT5 over expression inversely correlated with survival of GBM patients (r=-0.57, p=0.0001) and correlated with proliferation of GBM cell lines (r=0.81, p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1584.