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Published on: August 29, 2018
TIMELESS promotes glioma stemness and malignancy through JAK-STAT3 pathway
Yuichiro Kai1, Akito Tsuruta1, Takuto Inoki1
1Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, 3-1-1, Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.
The Journal of Biological Chemistry
|August 13, 2026
Summary
TIMELESS, a circadian clock protein, drives aggressive glioma growth by enhancing glioma stem cells (GSCs). Targeting the TIMELESS-JAK-STAT3 pathway offers a new strategy against treatment-resistant brain tumors.
Area of Science:
- Neuro-oncology
- Cancer biology
- Molecular mechanisms of cancer
Background:
- Gliomas, particularly glioblastoma (GBM), are aggressive brain tumors with poor prognosis.
- Glioma stem cells (GSCs) drive tumor progression, recurrence, and therapeutic resistance.
- Upstream regulators of GSC-sustaining pathways are not fully understood.
Purpose of the Study:
- To investigate the role of TIMELESS in glioma malignancy and its association with GSCs.
- To elucidate the molecular mechanisms by which TIMELESS influences glioma progression.
Main Methods:
- Analysis of TIMELESS mRNA expression in glioma patient cohorts.
- Genetic depletion of Timeless in an orthotopic mouse glioma model.
- Assessment of GSC properties and tumor aggressiveness.
- Investigation of the JAK-STAT3 signaling pathway activation.
Main Results:
- TIMELESS mRNA expression correlates with glioma grade and poor prognosis.
- Timeless depletion reduced tumor aggressiveness and prolonged survival in mice.
- Timeless upregulates JAK expression and STAT3 phosphorylation, enhancing glioma stemness.
- These findings were conserved in human GBM cells.
Conclusions:
- TIMELESS plays a critical role in sustaining glioma stemness and malignancy, independent of its circadian function.
- The TIMELESS-JAK-STAT3 axis represents a novel, non-canonical pathway in treatment-resistant glioma.
- Targeting TIMELESS may offer a therapeutic strategy for aggressive gliomas.
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