Glioblastoma multiforme (GBM) is the most common malignant brain tumor in adults with a median survival of 15-17 months. A major reason for the clinical outcome is the resistance of a subgroup of glioma cells to current therapies. This subpopulation, named glioma initiating cell (GIC), has stem cell like properties. Therefore, it is critical to understand the molecular mechanisms contributing to GIC stemness. Protein arginine methyltransferase 5 (PRMT5), which methylates proteins including histone and modifies their functions, is emerging as a key stemness factor for normal and cancer stem cells. Our recent data demonstrate that expression of PRMT5 increases with malignant progression of glioma. PRMT5 downregulation significantly inhibits sphere formation of GIC. The mechanism by which PRMT5 regulates the stemness of GIC has not been defined. PRMT5 downregulation results in decreased expression of Dual Specificity Phosphatase 4 (DUSP4). Decreased DUSP4 expression also significantly inhibited sphere formation of GIC. These findings support that PRMT5-DUSP4 axis plays a critical role in maintaining the stemness of GIC. DUSP4 is dimethylated in GIC. Our preliminary data suggest that PRMT5 regulates DUSP4 expression through modulation of DUSP4 protein stability. The role and mechanism of DUSP4 in GIC stemness is completely unknown. Preliminary data suggest that DUSP4 is involved in regulation of Sox4 tyrosine phosphorylation in GIC. Importantly, de-phosphorylated Sox4 enhances the expression of Sox2, a stemness transcription factor. Our overall goal is to define the role and mechanism of PRMT5-DUSP4 axis in the pathogenesis of GBM. The central hypothesis is that the PRMT5-DUSP4 axis plays an important role in maintaining the stemness of GIC. We hypothesize that PRMT5 stabilizes DUSP4 protein by dimethylation of DUSP4, which protects DUSP4 from degradation in GIC. We further hypothesize that DUSP4 regulates the activation of Sox4, a transcription factor. DUSP4 de-phosphorylates Sox4, and de-phosphorylated Sox4 has enhanced ability to induce Sox2 expression. To test our hypothesis, the following SPECIFIC AIMs are proposed.
In AIM 1, we will define the role of PRMT5-DUSP4 axis in maintaining stemness state of GIC and to determine whether Sox4 is required for the stemness state of GIC maintained by the PRMT5-DUSP4 axis.
AIM 2 aims to determine the molecular mechanism for PRMT5-mediated regulation of DUSP4 and Sox4.
AIM 3 aims to determine the role of PRMT5 and DUSP4 in gliomagenesis in GBM xenograft models and in human GBM. The completion of this project will define the novel role of PRMT5-DUSP4 axis in maintain the stemness of GIC and stimulate new paradigm in the pathogenesis of GBM. The findings will be helpful to evaluate the PRMT5-DUSP4 axis as a novel therapeutic target to improve treatment and prognosis in GBM patients.

Public Health Relevance

Glioblastoma is a highly malignant brain cancer with an average survival of 15 to 17 months despite aggressive treatment. Identification of novel therapeutic target is needed and will contribute to our arsenal to fight against this disease. We expect that our findings on protein arginine methyltransferase 5 will validate its status as a nove therapeutic target.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS095626-01A1
Application #
9052911
Study Section
Clinical Neuroimmunology and Brain Tumors Study Section (CNBT)
Program Officer
Fountain, Jane W
Project Start
2015-09-30
Project End
2020-08-31
Budget Start
2015-09-30
Budget End
2016-08-31
Support Year
1
Fiscal Year
2015
Total Cost
$321,563
Indirect Cost
$102,813
Name
University of Alabama Birmingham
Department
Neurology
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294