The roles of Cryptochrome-1: the circadian clock as a control point in cancer therapy

Abstract

In this review, we carefully describe the composition and operation of cryptochrome-1 (CRY1). We introduce four related signaling pathways, namely cAMP/PKA/CREB signaling way, HIFα signaling way, NF-κB signaling way, STAT3 signaling way, FOXO signaling pathway and Hedgehog (HH) signaling pathway. We also emphasize the current understanding of the complex roles CRY1 plays in the progression of various solid tumors. We propose that its function represents a novel therapeutic target that could pave the way for new cancer treatments. Additionally, we summarize three emerging therapeutic strategies based on the roles of CRY1: targeting CRY1 with small molecules, using CRY1 as diagnostic and therapeutic tools, and promoting drug efficacy through CRY1 modulations. It is imperative to underscore the significance of conducting more extensive research to translate the insights obtained from cellular and animal models into practical human applications, ultimately enhancing therapeutic outcomes.

Keywords: CRY1; Cancer; Circadian clock; In Silico; Signaling pathway.

Fig. 1

Schematic diagram of the circadian clock entrainment pathways. The mammalian circadian clock operates through a TTFL present in nearly all cells. The central clock in the SCN synchronizes peripheral clocks through electrical, endocrine and metabolic signals. Core clock components BMAL1 and CLOCK/NPAS2 activate expression of DEC, PER and CRY genes. PER-CRY heterodimers then inhibit BMAL1-CLOCK/NPAS2 activity, creating a negative feedback loop. DEC proteins reinforce rhythmicity by competing for E-box binding. BMAL1-CLOCK/NPAS2 also activates Rorα and Rev-erbα expression, which reciprocally regulate clock gene transcription to form secondary feedback loops. CRY expression shows diurnal variation in the eye and SCN Abbreviations: TTFL, transcription-translation feedback loop; CLOCK, circadian locomotor output cycles kaput; BMAL1, brain and muscle ARNT-like protein 1; CRY, cryptochrome; PER, period; RORs, retinoic acid receptor-related orphan receptors; NPAS2: Neuronal PAS domain protein 2; SNC, suprachiasmatic nucleus.

Fig. 2

Mechanism of related signaling pathway. CRY1 regulates key oncogenic and immunomodulatory pathways, including: (1) cAMP/PKA/CREB signaling where CRY1 inhibits melanogenesis through PKA-mediated CREB phosphorylation; (2) HIF-1α signaling through CRY1-mediated destabilization of HIF-1α protein; (3) NF-κB signaling via CRY1-induced GSK3β interaction and inhibition of NF-κB prosurvival signaling; (4) STAT3 signaling via CRY1 silencing-induced NANOG reduction and p53 activation; (5) FOXO signaling via CRY1-induced FOXO1 ubiquitination and degradation; and (6) HH signaling where CRY1 inhibits Gli transcription factor nuclear translocation. These pathways collectively demonstrate CRY1’s multifaceted role in tumor progression Abbrevation: CREB, cAMP-response element binding protein; CRY, Cryptochrome; TNF-α, tumor necrosis factor α; TLR, toll-like receptors; p-p65, phosphorylated p65; FOXO, forkhead box O; HH, Hedgehog; SHH, Sonic Hedgehog; IHH, Indian Hedgehog; DHH, Desert Hedgehog.