Glioblastoma (GBM) is the most common and lethal primary brain tumor with dismal prognosis. GBM displays remarkable cellular heterogeneity with a population of glioma stem cells (GSCs) at the apex of the differentiation hierarchy. Because GSCs promote tumor angiogenesis, cancer invasion, therapeutic resistance and tumor recurrence, eliminating GSCs or inducing their differentiation may effectively improve GBM treatment. The stem cell-like property of GSCs is maintained by a set of core transcriptional regulators including c-Myc. Myc plays a critical role in promoting GBM malignant growth and radioresistance. C-Myc is not only regulated at the transcriptional level but also tightly controlled by post-translational modifications. Our preliminary data indicate that c-Myc is ubiquitinated by the E3 ubiquitin ligase, FBXL14, and targeted for degradation in non-stem glioma cells. In GSCs, c-Myc protein is stabilized through the deubiquitination mediated by USP13 (Ubiquitin-Specific Protease 13). Importantly, USP13 is preferentially expressed in GSCs relative to non-stem glioma cells and neural progenitor cells. Targeting USP13 by shRNA markedly reduced c-Myc protein, promoted GSC differentiation, disrupted GSC maintenance, and potently inhibited GSC tumorsphere formation. These data indicated that USP13 plays a crucial role in maintaining GSC self-renewal and tumorigenic potential through Myc stabilization. We hypothesize that USP13 antagonizes FBXL14 to stabilize c-Myc and promote the maintenance of GSCs, and that functional inhibition of USP13 disrupts GSCs to suppress GBM tumor growth. We will test our hypothesis by pursuing three specific aims: 1. Determine the role of USP13 in regulating c-Myc to maintain GSC tumorigenic potential; 2. Define the role of FBXL14 in c-Myc degradation and tumor suppression of glioma cells; 3. Evaluate the therapeutic benefit of targeting USP13 in GBM therapy. The goal of this proposal is to evaluate the therapeutic potential of disrupting GSCs through USP13 inhibition in a preclinical setting. As c-Myc oncoprotein is a transcription factor and is required for normal cell proliferation, therapeutic targeting of c-Myc is difficult. However, targeting its upstream regulator USP13 to selectively disrupt c-Myc in GSCs could provide a practical approach. We will determine whether targeting deubiquitinase USP13 can serve as an effective therapeutic strategy to improve GBM treatment.

Public Health Relevance

Glioblastoma (GBM) is among the deadliest of all human cancers. Despite optimal treatments, the median survival of GBM patients remains less than 16 months due to therapeutic resistance and rapid tumor recurrence. C-Myc oncoprotein plays critical roles in promoting malignant growth and therapeutic resistance in GBM. As c-Myc is a transcription factor and is required for normal cell growth, therapeutic targeting of c-Myc is very difficult. We have identified a c-Myc upstream regulator called USP13 (a deubiquitinating enzyme) that is preferentially expressed in glioma stem cells (GSCs). Thus, targeting USP13 to selectively disrupt c-Myc in GSCs could provide a unique approach. Our goal is to evaluate the therapeutic potential of USP13 inhibition in a preclinical study. We will determine whether targeting USP13 can serve as an effective therapeutic strategy to improve treatment for GBM patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS099175-03
Application #
9513063
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Fountain, Jane W
Project Start
2016-09-30
Project End
2021-06-30
Budget Start
2018-07-01
Budget End
2019-06-30
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
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