Key Takeaways & Executive Findings
- •• Cryptochromes (CRY1 and CRY2) are core components of the circadian clock and play dual roles in cancer, acting as tumor suppressors or promoters depending on cancer type and context. • Disruption of circadian rhythms is linked to cancer development, and CRY proteins influence key cancer hallmarks including cell proliferation, apoptosis, DNA damage response, and metabolism. • Clock genes, including CRYs, modulate the tumor microenvironment (TME) by affecting immune cell infiltration, angiogenesis, and inflammation, thereby impacting tumor progression and therapy response. • Clock-based therapeutic strategies, such as chronomodulated chemotherapy and targeting CRY proteins, hold promise for improving cancer treatment efficacy and reducing side effects.
Abstract
The circadian rhythm is a phenomenon in which physiological, behavioral, and biochemical processes within an organism naturally fluctuate over a period of approximately 24 hours. This phenomenon is ubiquitous in living organisms. Disruption of circadian rhythms in mammals leads to different diseases, such as cancer, and neurodegenerative and metabolic disorders. In specific tissues, numerous genes have been found to have circadian oscillations, suggesting a broad role for rhythm genes in the regulation of gene expression. This review systematically summarizes the role of cryptochromes (CRYs) in the initiation and progression of different types of cancer and discusses the relationships between clock genes and the tumor microenvironment (TME), as well as clock-based therapeutic strategies.
1. Introduction
Organisms typically experience regular cycles of light and darkness, with the alignment of behavior to this circadian rhythm being advantageous for the prevalence of circadian phenomena. The molecular mechanisms of the circadian clock involve the production of Transcription-translation feedback loops (TTFLs), which interact with a set of CLOCK proteins to regulate the expression of specific target genes and their products in a circadian pattern. The core TTFL is modulated by four CLOCK proteins, including two activators, the circadian locomotor output cycles kaput (CLOCK) and brain-muscle binding protein 1 (BMAL1), and two inhibitors, period circadian protein homolog (PER) and CRY. The PER and CRY proteins combine to form a heterodimer in the cytoplasm, which then moves to the nucleus to hinder CLOCK/BMAL1 transcriptional activation. Following the degradation of the PER/CRY complex through a ubiquitin-dependent pathway, CLOCK/BMAL1 is liberated, initiating a new cycle. This 24-hour process establishes a fundamental circadian rhythm within the body (Figure 1) [1].
Numerous genes have been shown to exhibit circadian oscillations in tissues, indicating the significant role of circadian genes in gene expression regulation. Disruptions in mammalian circadian rhythms have been linked to various diseases, such as cancer, neurodegenerative disorders, and metabolic conditions [2,3]. This review examines the impact of CRYs on the onset and progression of cancer and explores the associations between clock genes and the tumor microenvironment (TME), along with clock-based therapeutic strategies.
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Shuzhao Zhang, Xue Chen, Jiayi Li, An’an Xu, Ann M. Bode, Xiangjian Luo (2026). The role of cryptochrome (CRY) in cancer: molecular mechanisms and clock-based therapeutic strategies. Acta Biochimica et Biophysica Sinica. https://doi.org/10.3724/abbs.2025025
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Frequently Asked Questions
What is the role of cryptochrome (CRY) in cancer?
Cryptochromes (CRY1 and CRY2) are core components of the circadian clock that regulate gene expression. In cancer, they can act as tumor suppressors or promoters depending on the cancer type, influencing cell proliferation, apoptosis, DNA repair, and metabolism.
How do clock genes affect the tumor microenvironment?
Clock genes, including CRYs, modulate the tumor microenvironment by affecting immune cell infiltration, angiogenesis, and inflammatory responses, thereby influencing tumor progression and response to therapy.
What are clock-based therapeutic strategies for cancer?
Clock-based therapeutic strategies include chronomodulated chemotherapy (timing drug administration to the circadian rhythm) and targeting clock proteins like CRY to disrupt cancer cell proliferation or sensitize them to treatment.
Why is circadian disruption linked to cancer?
Circadian disruption alters the expression of clock-controlled genes involved in cell cycle, DNA repair, and metabolism, leading to increased cancer risk and progression. Shift work and chronic jet lag are examples of circadian disruptors.
What is the significance of CRY in cancer therapy?
CRY proteins are potential therapeutic targets because they are involved in cancer cell survival and proliferation. Modulating CRY activity could enhance the efficacy of existing treatments or provide new avenues for targeted therapy.
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