Chronotype and Cancer: Emerging Relation Between Chrononutrition and Oncology from Human Studies

Abstract

Fasting-feeding timing is a crucial pattern implicated in the regulation of daily circadian rhythms. The interplay between sleep and meal timing underscores the importance of maintaining circadian alignment in order to avoid creating a metabolic environment conducive to carcinogenesis following the molecular and systemic disruption of metabolic performance and immune function. The chronicity of such a condition may support the initiation and progression of cancer through a variety of mechanisms, including increased oxidative stress, immune suppression, and the activation of proliferative signaling pathways. This review aims to summarize current evidence from human studies and provide an overview of the potential mechanisms underscoring the role of chrononutrition (including time-restricted eating) on cancer risk. Current evidence shows that the morning chronotype, suggesting an alignment between physiological circadian rhythms and eating timing, is associated with a lower risk of cancer. Also, early time-restricted eating and prolonged nighttime fasting were also associated with a lower risk of cancer. The current evidence suggests that the chronotype influences cancer risk through cell cycle regulation, the modulation of metabolic pathways and inflammation, and gut microbiota fluctuations. In conclusion, although there are no clear guidelines on this matter, emerging evidence supports the hypothesis that the role of time-related eating (i.e., time/calorie-restricted feeding and intermittent/periodic fasting) could potentially lead to a reduced risk of cancer.

Keywords: cancer; chronotype; circadian rhythm; gut microbiota; metabolic dysregulation; sleep; time-restricted eating.

Figure 1

Major genes demonstrating circadian expression potentially involved in cancer biology. (a) WEE1 is an important kinase involved in controlling the G2/M transition of the cell cycle. It works by adding phosphate groups to CDK1 (Cyclin-Dependent Kinase 1), which inhibits its activity and prevents the cell from entering mitosis too early. When WEE1 expression is disrupted, it can lead to abnormal cell cycle progression and increased tumor cell growth, especially in both blood-related and solid cancers. The circadian regulation of WEE1 ensures that cell cycle checkpoints function correctly at various times of the day, helping to prevent errors in DNA replication that could result in cancer. Disruptions in WEE1 expression in tumors can cause uncontrolled cell division and genomic instability. (b) The MYC proto-oncogene produces transcription factors that regulate the transition from the G0 to G1 phase of the cell cycle. As a key regulator of cell growth and division, MYC is often overexpressed in many types of cancer. Excessive MYC activity promotes cell proliferation by activating genes that drive the cell cycle forward. The circadian regulation of MYC helps balance cell growth and division, but when this regulation is disrupted, it can lead to uncontrolled cell division, a hallmark of cancer. (c) Cyclin D1 is crucial for the G1/S transition in the cell cycle, where it activates CDK4 and CDK6, leading to the phosphorylation of the retinoblastoma protein and promoting cell cycle progression. Cyclin D1 is often overexpressed in various cancers, which accelerates entry into the S phase and boosts cell proliferation. Its circadian regulation ensures the proper timing of its expression during the cell cycle, but when circadian rhythms are disrupted, Cyclin D1 regulation is lost, which can contribute to cancer progression. (d) CDKN1A, or p21, is a cyclin-dependent kinase inhibitor that regulates the cell cycle by preventing cyclin–CDK complexes from functioning. As a tumor suppressor, p21 helps arrest the cell cycle, but its expression can be dysregulated in different cancers. In some cancers, p21 is overproduced, which may help cells resist apoptosis, while in others, its expression is too low, leading to unchecked cell growth. The circadian expression of p21 ensures the proper regulation of the cell cycle, but the disruption of circadian rhythms can impair this regulation, potentially driving tumor formation. (e) p53 is a tumor suppressor gene essential for maintaining genomic stability by controlling cell cycle arrest, DNA repair, and apoptosis. Disruptions to the circadian rhythm can impair p53′s function, increasing the risk of genomic instability and cancer. Research shows that altered circadian rhythms reduce p53 activity, preventing the cell from halting the cycle in response to DNA damage, allowing for continued proliferation despite genetic mutations. The loss of p53 function is a key factor in many cancers, and circadian disruptions can worsen this issue, elevating the likelihood of cancer development. (f) Vascular Endothelial Growth Factor (VEGF) regulates normal cell growth and angiogenesis, the formation of new blood vessels. In cancer, VEGF promotes the growth of blood vessels that supply tumors with oxygen and nutrients, supporting tumor expansion. Circadian rhythms influence VEGF expression, and when circadian timing is disrupted, VEGF levels can rise, enhancing angiogenesis and tumor metastasis. (g) Growth Arrest and DNA Damage-Inducible Protein alpha (GADD45a) plays a role in responding to cellular stress and DNA damage. It helps repair DNA and control the cell cycle by interacting with cdc2/cyclinB1 kinases to inhibit cell cycle progression during the G2/M and S phases. GADD45a is often underexpressed in cancers, and its circadian regulation ensures it is available to repair DNA damage when needed. Disruptions in GADD45a expression due to circadian misalignment can prevent effective DNA repair, leading to genomic instability and promoting cancer progression. (h) PDGF Receptor (PDGFr) is a receptor tyrosine kinase involved in cellular growth, survival, and migration. PDGFr plays a role in cancer progression by promoting tumor cell proliferation, migration, and invasion. The dysregulation of PDGF receptor signaling has been linked to various cancer types, and circadian disruption can alter its expression, enhancing tumor growth and metastasis. (i) MDM2 is a negative regulator of p53, forming a feedback loop that controls p53 levels by promoting its degradation. In healthy cells, MDM2 prevents the accumulation of excess p53, ensuring proper cell cycle control. However, MDM2 is often overexpressed in cancers, leading to reduced p53 activity and the evasion of cell cycle arrest and apoptosis. The circadian regulation of MDM2 ensures this feedback loop works as intended, but the disruption of circadian rhythms can prevent proper p53 regulation, allowing damaged cells to proliferate and contribute to cancer development.