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Gene & Protein in Disease Pediatric glioma circadian clock genes

timing information they generate and disseminate, as well in gastric cancer, and its elevated expression in adult
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as any cell regulation they provide independent of the gliomas is considered a risk factor. TIMELESS shows
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clock, particularly in cancer cells that frequently have a higher expression in high-grade than low-grade gliomas
compromised circadian clock mechanism. Furthermore, and adjacent non-tumor tissue, in agreement with
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some of the significant differences in gene expression TIMELESS expression we observed in pediatric gliomas.
discussed here might depend on the phase of the circadian Because it regulates DNA replication and maintains cell
cycle when the glioma samples were collected, which was migration in other cancers, therapies should be explored
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not available in this analysis. that manipulate the TIMELESS protein or its specific
Starting with one of the most highly repressed clock binding partners, such as TIMELESS interacting protein
genes in the bulk-tumor data of this study, RORB appears (TIPIN). Because TIMELESS is reported to suppress gene
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to be a promising target for additional therapies developed induction by the BMAL1/CLOCK dimer, a strategy may
to treat pediatric and adult gliomas. It was significantly be developed like that in which CRY proteins are elevated
underexpressed relative to non-tumor tissue in eight of to interfere with the dimer’s induction of genes through
the ten bulk-tumor tumor studies examined (not Kamoun E-boxes. Separate TIMELESS-elevating and CRY-elevating
et al. and de Bont et al. ). Nevertheless, according to the compounds might be particularly effective when used in
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pHGG scRNA-seq dataset, RORB was one of the more combination to target the same process, which appears
highly expressed genes when compared with the rest of the critical for cancer cell survival. Altered sleep could be
core clock gene set. It was one of the least widely expressed one unintended effect because of reports of TIMELESS
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genes of the core circadian gene set when comparing mutations affecting sleep onset. A recent study indicates a
cell types in the MB scRNA-seq results. Along with its role for TIMELESS in hippocampal learning and memory
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role in the circadian timing mechanism, RORB may functions through glutamate receptors, which should be
regulate tumor growth through interaction with the Wnt considered when developing a cancer therapy.
intracellular signaling pathway. However, any treatment
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designed to increase RORB protein levels or stability might 4.2. Differences in clock gene expression between
induce ARNTL, which would be predicted to favor GSC adult and pediatric gliomas
survival. 4.2.1. ARNTL and GSCs
CRY2 may be an effective drug target for pediatric BMAL1, the product of ARNTL, and its dimerization
gliomas as it was significantly underexpressed relative to partner CLOCK are together considered critical for
non-tumor tissue in 10 of the 11 pediatric bulk-tumor circadian rhythm generation and survival of adult GBM
datasets examined. Pharmacological treatments that cells. Therefore, it was unexpected that ARNTL would
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prevent CRY protein degradation, thereby allowing it to be significantly downregulated in the bulk-tumor pediatric
suppress BMAL1/CLOCK functions, have been shown to datasets, including pediatric GBM. Nevertheless, BMAL1
be effective in suppressing the proliferation of adult GSCs is reported to act as a tumor suppressor in an epithelial-
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and, we predict, pediatric glioma cells as well. type GBM cell line (LN229) used in a mouse xenograft
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The TIMELESS gene was unique in that it was the most model, which agrees with the significant ARNTL
overexpressed gene in pediatric gliomas, indicating it is a suppression we detected. It is possible that BMAL1
promising target for developing treatments that make use suppresses replication of cancer cells in the epithelial
of the circadian clock through chronopharmacology or state and is then upregulated during EMT, through which
more conventional, non-circadian therapies. Among the mesenchymal GSCs are produced. The lower ARNTL
medulloblastoma subgroups, TIMELESS expression was expression in the OPC-like cells relative to the mesenchymal
significantly higher in the G3 and G4 subgroups relative cell group of the pHGG scRNA-seq study agrees with this
to SHH, suggesting they would be most impacted by possibility. The reduced overall ARNTL expression in the
treatments suppressing TIMELESS. On the other hand, bulk tumor data might be explained by a large percentage
TIMELESS may be at a minimal functioning level in the of non-stem cells, such as OPCs, in the tumor mass. It has
SHH-expressing cells, indicating greater vulnerability of been proposed that tissue-specific conditions and cell-cell
this subgroup to TIMELESS suppression, if the protein interactions may determine whether ARNTL and other
supports cancer cell survival. Results from both the clock genes act as either tumor suppressors or, instead as
pHGG and MB scRNA-seq studies indicated that a greater oncogenes. 6
understanding of the functioning of TIMELESS activity in The GSCs generated by EMT may depend on elevated
gliomas is needed. and perhaps rhythmic ARNTL expression. In agreement
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Increased TIMELESS expression has been reported with this speculation, GSC cell cultures have provided

Volume 4 Issue 2 (2025) 14 doi: 10.36922/gpd.4112