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Gene & Protein in Disease Pediatric glioma circadian clock genes

evidence that BMAL1 and other clock proteins enable GBM it is conceivable that rhythm generation may be absent
cell survival. In contrast, nasopharyngeal carcinoma despite elevated clock gene expression if certain critical
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cells show greater radioresistance and enhanced post- clock genes are constantly activated, thus preventing the
EMT properties (motility, invasiveness) as BMAL1 levels necessary troughs in their rhythms and completion of the
decline. Regulation by BMAL1 and CLOCK appears to oscillation. Adequate clock gene expression at least at a
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differ between cancer cell types. BMAL1 also serves in minimal level is a necessary but not sufficient criterion for
the EMT of non-cancerous cells during development. For circadian rhythm generation, and overexpression could
example, a recent study showed that trophoblasts rely on block rhythmicity.
BMAL1 to undergo EMT, which is needed to anchor the
placenta in the uterus, and that CRY2 suppresses this EMT 4.2.2. PER genes and GSCs
event. 81 In bulk tumor datasets, the pediatric GBM did not show

Pharmacological methods that can selectively control reduced PER2 and PER3 expression relative to normal brain
BMAL1 or E-box regulation of CCGs are promising tissue, which differs from the adult GBM data examined
treatments for gliomas, particularly to repress EMT and here, and reported suppression of the PER genes in many
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resulting cell motility and invasiveness. However, the but not all types of cancers. Although PER protein was
CRY protein-stabilizing drug KL001 that suppresses adult not measured, the apparently normal PER gene expression
glioma cell growth might be less suitable for pediatric in the pediatric gliomas increases the possibility that these
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gliomas, where ARNTL and ARNTL2 were found to be cells include functional circadian clocks. Nevertheless,
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already repressed; additional interference through elevated reported rhythms in cell cultures derived from GBM
CRY proteins and reduced BMAL1 functioning may not indicate that even the suppressed PER gene expression in
be beneficial. However, we did not see evidence of ARNTL adult GBM is adequate for circadian rhythm generation.
suppression in the scRNA-seq results, although direct The importance of considering PER2 expression levels in
comparisons with expression in normal tissue were not cancer cells depends in part on its ability to bind to and
provided. stabilize the tumor suppressor p53, but how it regulates
p53 activities is still being actively explored. 82
The difference in ARNTL expression between
pediatric and adult GBM observed here in the bulk These transcriptomic results need to be confirmed
tumor data should be explored further and may indicate through quantitative measures of the expressed proteins
that a unique strategy is needed for circadian clock- and their rhythmicity. However, information on the
based treatments that would be specifically designed for levels of clock proteins in pediatric proteins is lacking.
pediatric tumors. Notably, DBP, HLF, and TEF, which are If pediatric gliomas have more robust and less disrupted
induced by BMAL1 and CLOCK, were also significantly circadian rhythms than adult gliomas, then anticancer
repressed in the pediatric and adult gliomas, suggesting treatments might prove effective by manipulating the
that overall CCG regulation by BMAL1 may be clock mechanism that apparently supports cell survival
impaired. This deficiency might be corrected to improve and helps to maintain the stem cell state. The observed
patient outcomes through a specific pharmacological downregulation of ARNTL and its paralog ARNTL2 in
intervention. DBP, HLF, and TEF were downregulated, pediatric tumors might, however, be impeding the ability
and NFIL3 was upregulated in adult GBM, consistent with of pediatric GBM tumors to generate rhythms.
the reported antagonistic relationship between NFIL3 Along with PER2, PER1 is typically downregulated
and the other three transcription factors. This inverse in gliomas and other tumors, for example, those in
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relationship was not observed in the pediatric gliomas. breast, prostate, and oral squamous cell cancers. 84-86
Although ARNTL was suppressed or near normal levels PER1 expression was reported in only one of the five
in the MB datasets, it was elevated in Group 3 relative to pediatric datasets that were compared with non-tumor
the SHH and WNT subgroups (Cavalli, Robinson, and tissue. Surprisingly, it was elevated in one of the four
Northcott datasets), suggesting differences in how the adult GBM datasets encompassing this gene, unlike the
associated tumor cell types might respond to ARNTL- overall PER2 and PER3 downregulation in adult GBMs.
modulating treatments. The elevated PER1 expression might be explained by
The higher expression of clock genes in Groups 3 and 4 how PER1 transcriptional regulation differs from that of
in relation to the other medulloblastoma subtypes suggests PER2 because its promoter responds more effectively to
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that they have adequate expression to sustain circadian intracellular signals acting through Ca and cAMP. This
rhythms intrinsic to these cells, although circadian pathway is instrumental in the ability of neurons in the
rhythmicity needs to be demonstrated. Nevertheless, SCN to respond to direct retinal projections through the

Volume 4 Issue 2 (2025) 15 doi: 10.36922/gpd.4112