# Role of Quaking gene in regulating the niche-independent stemness of glioma stem cells

> **NIH NIH R37** · UNIVERSITY OF TX MD ANDERSON CAN CTR · 2022 · $366,000

## Abstract

PROJECT SUMMARY
 Glioblastoma is the most common type of brain tumor and is currently incurable. The lack of effective
treatments highlights the urgent need for identifying mechanism-based therapeutic approaches. Substantial
experimental evidence has recently revealed a population of neural stem cell (NSC)-like glioma stem cells
(GSCs) that possess an inexhaustible ability to self-renew as the “root” of glioblastoma. Like NSCs, GSCs are
known to maintain their stemness by interacting with niches, which provides proper cues to prevent them from
differentiating. But how GSCs manage to sustain their self-renewal capacity in the sub-optimal environment
outside the niches, particularly during the process of invasion and migration, remains less clear. As part of our
effort to identify potential glioma suppressors involved in the regulation of central nervous system
development, we discovered that RNA binding protein Quaking (QKI) is a major regulator of NSC and GSC
self-renewal. QKI is frequently deleted or mutated in human glioblastomas. Using a newly established animal
model, we genetically demonstrated that QKI is a bona fide glioma suppressor whose depletion strongly
promotes gliomagenesis. Functionally, we revealed that QKI is a key regulator of cellular endocytosis that
controls receptor trafficking, degradation, and signaling desensitization. Specifically, we showed that depletion
of QKI led to the enrichment of cytoplasmic membrane-bound Wnt and Notch receptors (Frizzled and Notch1)
and subsequent signal hyperactivation. Given that Wnt and Notch1 are two major signaling cascades involved
in maintaining NSC and GSC stemness against differentiation, we propose that QKI modulates NSC and GSC
self-renewal and gliomagenesis by controlling endolysosome-mediated Frizzled and Notch1 degradation. To
test this hypothesis, in Aim 1, we will determine how QKI regulates the endolysosome-dependent degradation
of Wnt receptor Frizzled in NSCs and GSCs. In Aim 2, we will delineate the molecular mechanism by which
QKI modulates RNA alternative splicing of the endocytic regulator Numb and the endolysosomal Notch1
degradation. Together, these studies will elucidate the molecular mechanisms underlying QKI-mediated
endolysosome-dependent regulation of Wnt and Notch1 signal activation, and more importantly, they will
contribute to the development of therapeutic strategies that specifically target QKI-depleted glioblastoma.

## Key facts

- **NIH application ID:** 10310491
- **Project number:** 5R37CA214800-05
- **Recipient organization:** UNIVERSITY OF TX MD ANDERSON CAN CTR
- **Principal Investigator:** Jian Hu
- **Activity code:** R37 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $366,000
- **Award type:** 5
- **Project period:** 2017-12-01 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10310491

## Citation

> US National Institutes of Health, RePORTER application 10310491, Role of Quaking gene in regulating the niche-independent stemness of glioma stem cells (5R37CA214800-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10310491. Licensed CC0.

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