Review ArticleReview

Major roles of the circadian clock in cancer

Chen Huang, Chenliang Zhang, Yubin Cao, Jian Li and Feng Bi
Cancer Biology & Medicine January 2023, 20 (1) 1-24; DOI: https://doi.org/10.20892/j.issn.2095-3941.2022.0474

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Figures

  • Figure 1
    Figure 1

    Molecular mechanisms of the circadian clock. The positive stimulus factor TTFL is composed of CLOCK, BMAL1, and its paralog NPAS2. This complex binds the target E-box (CTGCAG) sequence, thereby promoting the expression of transcription inhibitor CRY1/2 and PER1/2/3. CRY and PER serve as negative stimuli for TTFL. Two different stimuli form 2 complexes with opposite functions: the CLOCK-BMAL1 transcription activator and CRY-PER transcription inhibitor. Their growth and decline show a clear circadian rhythm. The CRY-PER complex enters the nucleus and inhibits the function of CLOCK-BMAL1 complex. the CLOCK-BMAL1 complex acts on the nuclear receptor Rev-ERBα/β (NR1D1/2) and RORs, and regulates their expression levels, thereby affecting BMAL1 expression and constituting the second feedback loop. Additionally, this loop is controlled by the kinase CK1δ/ε and ubiquitin ligases. 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. (In this picture, the dashed line indicates the boundary between the day and night phases, and the meaning of the remaining arrows is shown in the figure.)

  • Figure 2
    Figure 2
    Figure 2

    Expression analysis of BMAL1 in tumor tissues. The expression distribution of the BMAL1 (ARNTL) gene in tumor and normal tissues. The abscissa represents different tumor tissues, and the ordinate represents the gene expression distribution. Different colors represent different groups. *P < 0.05, **P < 0.01, ***P < 0.001, with asterisks indicating significance. The Wilcoxon test indicated that the 2 sample groups were dominant.

  • Figure 3
    Figure 3

    Mechanisms of the circadian clock in cancer. The circadian clock plays an important role in tumorigenesis, tumor growth, metastasis, tumor immune escape, and other processes by regulating various biological functions, such as apoptosis and proliferation. Among them, many signaling pathways, such as the AMPK/mTOR pathway, Wnt/β-Catenin pathway, and NF-κ B pathway, as well as molecules, such as Hif-1α, P53, and PD-1 may play important roles.

  • Figure 4
    Figure 4

    Functions and effects of BMAL1 in cancer. The known and potential mechanisms of BMAL1 are involved in all cancer stages, including protein synthesis, tumorigenesis, tumor progression, and metastasis. This figure was created with biorender.com.

  • Figure 5
    Figure 5
    Figure 5

    Immune-associated analysis and tumor mutational burden of BMAL1. (A) Tumor mutation burden: Spearman’s correlation analysis of TMB and BMAL1 gene expression. The transverse coordinates represent the correlation coefficient between genes and TMB, the ordinate coordinates represent different tumors, the circular point size represents the correlation coefficient, and different colors represent P-value aboriginality: bluer color in the diagram indicates smaller P-values. (B) The xCell immune infiltration score in multiple tumor tissues, and Spearman correlation analysis heatmap of BMAL1 (ARNTL) gene expression. The abscissa represents different tumor tissues, the ordinate represents different immune infiltration scores, different colors represent the correlation coefficient, negative values represent negative correlations, and positive values represent positive correlations. Stronger correlation is indicated by deeper color. *P < 0.05, **P < 0.01, **P < 0.001, with asterisks indicating significance. The dominance of the 2 sample groups passed the Wilcoxon test.

  • Figure 6
    Figure 6

    BMAL1 and prognosis of cancer. Forest plot: single-factor Cox analysis results for a single gene in multiple tumors, P-value, risk coefficient HR, and confidence interval. Abb: ACC, adrenocortical carcinoma; BLCA, bladder urothelial carcinoma; BRCA, breast invasive carcinoma; CESC, cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOL, cholangiocarcinoma; COAD, colon adenocarcinoma; DLBC, lymphoid neoplasm diffuse large B-cell lymphoma; ESCA, esophageal carcinoma; GBM, glioblastoma multiforme; HNSC, head and neck squamous cell carcinoma; KICH, kidney chromophobe; KIRC, kidney renal clear cell carcinoma; KIRP, kidney renal papillary cell carcinoma; LAML, acute myeloid leukemia; LGG, brain lower grade glioma; LIHC, liver hepatocellular carcinoma; LUAD, lung adenocarcinoma; LUSC, lung squamous cell carcinoma; MESO, mesothelioma; OV, ovarian serous cystadenocarcinoma; PAAD, pancreatic adenocarcinoma; PCPG, pheochromocytoma and paraganglioma; PRAD, prostate adenocarcinoma; PEAD, rectal adenocarcinoma; SARC, sarcoma; SKCM, skin cutaneous melanoma; STAD, stomach adenocarcinoma; TGCT, testicular germ cell tumors; THCA, thyroid carcinoma; THYM, thymoma; UCEC, uterine corpus endometrial carcinoma; UCS, uterine carcinosarcoma; UVM, uveal melanoma.

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