# Ubiquitination and Deubiquitination of c-Myc in Glioblastoma

> **NIH NIH R01** · CLEVELAND CLINIC LERNER COM-CWRU · 2020 · $346,719

## Abstract

Summary
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.

## Key facts

- **NIH application ID:** 9975243
- **Project number:** 5R01NS099175-05
- **Recipient organization:** CLEVELAND CLINIC LERNER COM-CWRU
- **Principal Investigator:** Shideng Bao
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $346,719
- **Award type:** 5
- **Project period:** 2016-09-30 → 2022-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9975243

## Citation

> US National Institutes of Health, RePORTER application 9975243, Ubiquitination and Deubiquitination of c-Myc in Glioblastoma (5R01NS099175-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9975243. Licensed CC0.

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