TIMELESS promotes glioma stemness and malignancy through JAK-STAT3 pathway.
Overview
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
- Department of Clinical Pharmacokinetics, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka, Japan
Abstract
Gliomas are the most common primary tumors of the central nervous system. Among them, glioblastoma (GBM), a World Health Organization (WHO) grade 4 glioma, is the most aggressive form and remains one of the most lethal human cancers. Its poor prognosis is largely attributable to rapid progression, frequent recurrence, and profound therapeutic resistance, all of which are closely associated with glioma stem cells (GSCs). Although several signaling pathways sustaining GSC properties have been identified, upstream regulators that coordinate these pathways remain incompletely understood. TIMELESS, originally identified as a component of the circadian clock, has recently been implicated in the regulation of brain function and is aberrantly overexpressed in multiple cancer types; however, its role in glioma malignancy has not been defined. Here, we demonstrate that TIMELESS mRNA expression increases with glioma grade and is associated with poor prognosis across multiple glioma cohorts. Genetic depletion of Timeless suppressed tumor aggressiveness and prolonged survival in an orthotopic mouse glioma model by attenuating GSC properties. Mechanistically, TIMELESS enhanced stemness of glioma by upregulating Janus kinases (JAK) expression and promoting phosphorylation of signal transducer and activator of transcription 3 (STAT3). These effects were conserved in human GBM cells, supporting the relevance of TIMELESS-mediated signaling across species. Together, our findings uncover an unexpected, clock-independent function of TIMELESS in sustaining glioma stemness and malignancy and highlight the TIMELESS-JAK-STAT3 axis as a noncanonical mechanism that operates beyond the traditional circadian clockwork in treatment-resistant glioma.
Reproduced under the paper's license (CC BY), from the paper cited above.
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Data
Datasets cited
- geo:GSE336084, at NCBI GEO; found in “Data availability”
Data availability
All data supporting the results of the present study are included in the article.
The RNA-seq data generated in this study have been deposited in the Gene Expression Omnibus (GEO) database under accession number GSE336084 (https://
Reproduced under the paper's license (CC BY), from the paper cited above.
Versions
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Version 2, 28 September 2026
- Authors: added Tomoaki Yamauchi (0009-0001-2598-4566); removed Tomoaki Yamauchi
Version 1, 27 September 2026: the first record
Recorded: type, language, journal, volume, issue, pages, dates, 6 authors, 5 keywords, 3 funders, 48 references, 16 RRIDs.
Cite
This paper
Kai, Y., Tsuruta, A., Inoki, T., Yamauchi, T., Ohdo, S., & Koyanagi, S. (2026). TIMELESS promotes glioma stemness and malignancy through JAK-STAT3 pathway. The Journal of biological chemistry, 302(10), 113447. https://
BibTeX
@article{kai2026timeless
author = {Kai, Yuichiro and Tsuruta, Akito and Inoki, Takuto and Yamauchi, Tomoaki and Ohdo, Shigehiro and Koyanagi, Satoru},
title = {{TIMELESS promotes glioma stemness and malignancy through JAK-STAT3 pathway}},
journal = {The Journal of biological chemistry},
year = {2026},
month = aug,
volume = {302},
number = {10},
pages = {113447},
publisher = {American Society for Biochemistry and Molecular Biology},
issn = {0021-9258},
doi = {10.1016/
url = {https://
pmid = {42595109},
pmcid = {PMC13579946}
}
RIS
TY - JOUR
AU - Kai, Yuichiro
AU - Tsuruta, Akito
AU - Inoki, Takuto
AU - Yamauchi, Tomoaki
AU - Ohdo, Shigehiro
AU - Koyanagi, Satoru
TI - TIMELESS promotes glioma stemness and malignancy through JAK-STAT3 pathway
T2 - The Journal of biological chemistry
J2 - J Biol Chem
PY - 2026
DA - 2026/
VL - 302
IS - 10
SP - 113447
SN - 0021-9258
PB - American Society for Biochemistry and Molecular Biology
DO - 10.1016/
UR - https://
LA - en
ER -
CSL-JSON
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"language": "en",
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