Table 1 Core circadian clock markers and their demonstrated links to cancer hallmarks and immune function

 BMAL1/2 (ARNTL)

Positive regulator of circadian cycles

1. Downregulation [3] or mutation [4] upregulates MYC in vivo, knockout increases cellular senescence in vivo [5]

2. Knockdown upregulates cyclin D1 expression in vitro [6], downregulation accelerates cell cycling in vitro [7]

3. Downregulation decreases apoptosis in vitro [7], knockout permits uncontrolled Atg14-mediated initiation of autophagy in vivo [8]

4. Knockout causes SIRT1-mediated telomere shortening in vivo [9]

6. Downregulation promotes metastatic (i.e., rapidly proliferating) phenotype in vitro [7]

7. Downregulation permits upregulation of WEE1 and TP53 in vivo [3]

8. Knockdown reduces tumor NAD+ levels in vitro [10]

9. Knockdown induces expression of pro-inflammatory angiopoietin-like protein 2 in vivo [11], knockout permits uncontrolled proinflammatory T_H17 cell development via IL-21 in vivo [12], and alters T_H17 cell differentiation via RORγt and NFIL3 pathways in vivo [13]

 CLOCK

Positive regulator of circadian cycles

3. Knockout permits uncontrolled Atg14-mediated initiation of autophagy in vivo [8]

4. Knockdown reduces tumor NAD+ levels in vitro [10]

7. Knockout deregulates WEE1 transcription in vivo [14]

9. Knockout permits uncontrolled differentiation of T_H17 cells via RORγt and NFIL3 pathways [13]

10. Knockout reduces T_H1 cell counts in vivo [13]

 PER1/2/3 (period)

Repressor of circadian cycles

1. Knockout increases RAS expression in vivo [15], overexpression downregulates PI3K in vivo [16]

2. Overexpression inhibits tumor growth in vivo [16], downregulation causes overexpression of MYC in vivo [17], knockdown increases multiple cyclins in vitro [18, 19]

3. Knockout downregulates P53-mediated apoptosis in vivo [20]

4. Overexpression increases β-catenin in vivo [16]

5. Knockdown increases VEGF in vitro [21]

6. Downregulation activates EMT [22], TWIST1/2, SLUG, and ZEB1/2 in vitro [23]

7. Downregulation upregulates P53 in vivo and in vitro [17, 23], and upregulates WEE1 in vivo [3], while knockout deregulates rhythmic expression of WEE1 in vivo [15]

8. Downregulation reprograms metabolism (downregulates glycolysis and lactate excretion) in vivo [24]

9. Downregulation activates MMP1 in vitro [23], knockout increases IL-6 and TNF-α in vivo [15]

10. Downregulation increases immunosuppressive T_REG in primary in vivo tumors [25]

 CRY1/2 (cryptochrome)

Repressor of circadian cycles

2. Knockdown represses cyclin D1 expression [6], permits Rb phosphorylation [6], and inhibits ubiquitination and turnover of c-Myc in vitro [26]; mutation downregulates c-Myc in vivo [4]

3. Knockdown alters expression of BCL2 in vitro [27], knockout permits uncontrolled Atg14-mediated initiation of autophagy in vivo [8]

7. Knockout deregulates WEE1 transcription in vivo [14] knockdown leads to the accumulation of DNA damage [27] and alters p53 and p21 expression and transcription in vitro [28]; knockout elevates proinflammatory cytokines in vitro [29]

10. Downregulation increases immunosuppressive T_REG in primary in vivo tumors [25]

 RORA/B/C (retinoic acid receptor-related orphan receptor α/β/γ; NR1F1/2/3)

Enhances rhythmic expression of BMAL1 and BMAL2

7. Downregulation decreases P53 expression in vitro [30]

8. Mutation permits loss of HDAC3 co-repression of metabolism genes [31]

9. Knockdown impairs IL-17 expression and T_H17 cell development in vivo and in vitro [32], RORγ agonist activates T_H17 cells and attenuates immunosuppression in vitro [33]

 REV-ERBA/B (NR1D1/2)

Represses rhythmic expression of BMAL1 and BMAL2

2. Agonist suppresses cyclin A expression in vitro [34]

3. Agonist inhibits autophagy in vitro [35]

4. Agonist reduces apoptosis in vitro [36]

6. Downregulation increases cell proliferation, motility and micro-metastasis formation in vivo [3]

9. Knockdown impairs IL-17 expression and T_H17 cell development in vivo and in vitro [32], knockout alters T_H17 cell differentiation via RORγt and NFIL3 pathways in vivo [13], knockdown or agonist gate expression and release of IL-6 in vivo and in vitro [37]

 Glucocorticoids

Positive regulator of diurnal behaviors (e.g., activity); immunosuppressive

1. Reintroducing rhythmic expression decreases S-phase cycling in vitro [38], dysregulation induces epidermal growth factor receptor (EGFR) overexpression in vivo [39]

2. Dysregulation induces G1/S cell cycle progression markers MYC, CDK3, CCND3, CCND1 and CDT1; upregulates Rb expression, phosphorylation in vitro [6]

5. Dexamethasone inhibits tumor cell VEGF and IL-8 expression in vivo [40], stress-induced overexpression induces angiogenesis in vivo [41]

6. Overexpression induces metastatic colonization in vivo [42]

7. Stress-induced overexpression induces nitric oxide-mediated DNA damage in vivo [41]

8. High-dose dexamethasone decreases expression of glucose uptake and glycolysis genes in vivo [43]

10. High-dose dexamethasone decreases expression of anti-tumor immune response genes in vivo [43], over-expression by tumor cells suppresses immune cell function in vitro [44], stress-induced overexpression induces pro-tumorigenic M2 macrophage upregulation in vivo [41]

 Melatonin

Positive regulator of nocturnal behaviors (e.g., sleep)

1. Loss of expression permits greater EGFR/MAPK pathway activity in vivo [45]

3. Exposure reduces AMPK and autophagic activity in vitro [46]

4. Loss of expression permits cytotoxicity and apoptosis in vivo [45]

7. Suppression increases LINE-1 retrotransposon-induced DNA damage in vitro [47]

8. Dysregulation accelerates tumor metabolism, increases aerobic glycolysis in vivo [48]

9. Administration selectively activates T_H1 (IL-2 and IL-6 in lymphocytes and monocytes), but not T_H2, cells in vitro [49], and T_H17 differentiation via NFIL3 pathway [50]