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Gene & Protein in Disease Pediatric glioma circadian clock genes

DNA repair, etc., to occur at the appropriate time of day. Circadian clocks are particularly relevant to gliomas
Circadian timing allows the individual to anticipate when because circadian rhythms in gene activity have been
important external events occur while optimizing the measured in glioma cell lines derived from human and
timing of internal rhythmic processes. Most notable is the rodent tumors, as previously reviewed. Furthermore,
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sleep–wake cycle of animals in which sleep is timed, or clock gene expression in tumors formed from glioblastoma
gated, to begin and end near specific times by the master (GBM) cells implanted into the brains of live mice is
circadian clock in the hypothalamic suprachiasmatic synchronized with their circadian locomotor rhythms.
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nucleus (SCN). 2,3 The circadian rhythms in gliomas interact with multiple
Along with circadian rhythms in the acquired and metabolic processes of cancer cells that are typically altered
innate immune systems, the sleep cycle is fundamentally relative to normal cells. For example, the E-box sequence
important in oncogenesis and cancer progression, in gene promoters is regulated by members of multiple
mediated in part through nighttime release of the hormone transcription factor families including hypoxia-inducible
melatonin. Oncogenesis and poor patient outcomes have factor (HIF), which responds to the low oxygen levels in
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been attributed to chronically altered circadian rhythms tumors, c-MYC, which is a master regulator of cancer, and
of normal cells. Perhaps equally important are circadian the SNAIL, TWIST, and ZEB proteins that are induced in
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clocks within precancerous and transformed cells during metastatic cancer stem cells. Much remains to be clarified
cancer development. How the circadian clock impacts concerning the molecular interactions and roles of these
oncogenesis remains uncertain, but efforts are being made E-box binding regulators and circadian clocks.
to understand the relationship between disruptions in the Circadian rhythms are evident in the glioma stem
circadian timing system of the body and altered patterns of cells (GSCs) within cancer cell cultures and in tumor
circadian gene expression in transformed cells at different spheroid cultures derived from GSCs, 9,11,13 although the
stages of cancer progression. Less attention has been given non-stem cancer cells that form much of the tumor mass
to comparing clock gene regulation in very young and can also express circadian rhythms in vitro. GSCs have
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much older cancer patients. properties allowing them to resist chemical and radiation
Around half of protein-coding genes in mammals show cancer treatments, and can be identified through many
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a daily rhythm in gene expression depending on tissue stem cell marker proteins. GSCs generally divide slowly
type. Many of these oscillations are generated locally by or not at all, migrate and invade surrounding tissue, and
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circadian clocks within the cells of tissues and organs. A are responsible for metastasis and, in some cases, tumor
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major transcription factor generating rhythmic expression recurrence. GSCs are plentiful in specific subregions of
of the clock-controlled genes (CCGs) is BMAL1, expressed tumors, for example, the pseudopalisading cells around
by the core clock gene ARNTL. These CCGs are regulated necrosis and in perivascular niches of human GBM
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in part through an E-box sequence in their promoters that tumors. Not surprisingly, GSCs are an important target of
is activated when it binds a dimer formed by BMAL1 and new therapeutic interventions to suppress invasive gliomas
an additional transcription factor CLOCK. The PER1, PER2, and tumor recurrence.
CRY1, and CRY2 genes are directly induced through an Early studies with animal models, particularly rodents,
E-box (e.g., 5’-CANNTG-3’), and their protein products feed support the concept that disrupted circadian clocks
back to inhibit their own expression by interfering with the promote cancer. 17,18 Members of the human PER gene
activators BMAL1 and CLOCK, thereby producing the core family (PER1, PER2, and PER3) are underexpressed in
cycling of the circadian pacemaker. This negative feedback adult GBM, a highly lethal astrocytoma with the highest
loop of transcription and translation works with a second WHO stage (IV), and in other cancer types, although
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transcription-translation loop that rhythmically induces PER3 is not considered a component of the core circadian
ARNTL (at a separate phase from PER gene induction), mechanism. As recently reviewed, reduction in PER
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generating a circadian rhythm in BMAL1 abundance by gene expression or functional mutations of these genes is
inducing members of the ROR and REV-ERB transcription associated with more aggressive cancers, less differentiated
factors through E-box regulation. In some cells, ARNTL2 tumor cells, and poorer patient outcomes. 21-23 Loss of
can replace ARNTL, and NPAS2 can replace CLOCK. PER2 expression in response to hypoxia can also move
Pharmacological manipulation of CRY and REV-ERB breast cancer cells toward the epithelial-mesenchymal
proteins to suppress BMAL1 is a novel anticancer treatment. transition (EMT) that produces stem-like cancer cells with
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Several additional proteins modify the two transcription- increased motility and invasiveness. 24-26 What has yet to be
translation loops to control the period, amplitude, and thoroughly addressed, however, is whether impaired or
stability of the generated circadian rhythm. altered clock gene activity acts within cancer cells primarily

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