Table 1 Upstream regulators and targets of FOXM1 in gliomas
Name | Expression | Glioma type | Axis | Action of FOXM1 | Highlights |
|---|---|---|---|---|---|
Upstream regulators of FoxM1 | |||||
CXCL12 [42] | ↑ | GBM | CXCL12/AKT/FOXM1 | Induces FOXM1 expression by binding to CXCR4 | • ↑Cell invasion • Correlated with FOXM1 expression in human malignant glioma samples |
CXCL12/CXCR4 [68] | ↑ | GBM | CXCL12/CXCR4/ FOXM1 | - | • ↑TMZ resistance, migration, and invasion |
MELK [28] | ↑ | GBM | MELK/FOXM1 | Phosphorylation of FOXM1 is dependent on PLK1 | • FOXM1 is a substrate for MELK |
HSF1 [69] | ↑ | GBM | HSF1/FOXM1 | binding sites at FOXM1 promoter | • FOXM1 is required for G2-M phase progression • Protects cells from heat shock stress • HSF1 is the critical regulator of FOXM1 expression under heat shock stress |
FGFR1 [58] | ↑ | GBM | FGFR1/FOXM1 | – | • ↑Resistance of GSCs to ionizing radiation • FGFR1/FOXM1/EMT axis is implicated in tumor relapse in patients treated with chemo-radiotherapy |
α6-integrin [70] | ↑ | GBM | α6-integrin/ ZEB1 and YAP1/FGFR1/FOXM1 | - | • ↑Proliferation, neurospheres formation, and stemness • Associated with poor prognosis |
EZH2 [46] | ↑ | GBM | MELK/ FOXM1/EZH2 | Both FOXM1 and MELK increase EZH2 promoter activity | • ↑Radioresistance of GSCs |
PARP3 [71] | ↑ | GBM | PARP3/Rad51/FOXM1 | Rad51 binds to the promoter of FOXM1/PARP3 | • ↑DNA damage response • ↑Radioresistance • ↑Tumor growth in vivo • ↑Cell proliferation |
NOX4 [72] | ↑ | GBM | NOX4/ HIF-1α /FOXM1 | NOX4 induces FOXM1 by increasing mitochondrial ROS stabilization of HIF-1α | • ↑Aerobic glycolysis and proliferation • ↑Tumorigenesis in vivo |
POLE2 [73] | ↑ | GBM | POLE2/AURKA/FOXM1 | POLE2 induces AURKA-mediated FOXM1 de-ubiquitination | • ↑Proliferation and migration |
PHGDH [74] | ↑ | Grade I-IV | PHGDH/FOXM1 | PHGDH stabilizes FOXM1 protein at its N-terminal | • ↑Proliferation and invasion • Associated with poor prognosis |
CEP55 [75] | ↑ | GBM | CEP55 /Akt /FOXM1/ MMPs | – | • Correlated with the tumor grade • Invasion migration • TMZ resistance • Neurosphere formation • Stem-like cells’ self-renewal |
HMGA2 [76] | ↑ | GBM | HMGA2/FOXM1 | HMGA2 enhances the promoter activity of FOXM1 | • ↑Pericyte differentiation and invasive properties of glioma-initiating cells • ↑GIC cell-cycle progression and invasion |
SAT1 [47] | ↑ | Grade III-IV | SAT1/MELK/FOXM1 | SAT1 causes polyamine acetylation of MELK | • DNA dynamics • ↑Brain tumor stemness |
TRIM56 [77] | ↑ | GBM | TRIM56/FOXM1/RAD51 | TRIM56 enhances the stability of FOXM1 by deubiquitination | • ↓Radiosensitization • ↑ DNA repairment • Poor survival |
CKAP4 [78] | ↑ | GBM | CKAP4/Akt/FOXM1 | CKAP4 regulates FOXM1 expression through the AKT/ERK signaling pathway | • Positively correlated with tumor grade, advanced age, non-chemotherapy, IDH wildtype, non-codeletion of X1p19q, and unmethylated MGMT promoter • ↑ Proliferation, migration, and invasion of GBM cells |
STEAP3 [52] | ↑ | GBM | TfR/STAT3/FoxM1 | STEAP3 regulates FOXM1 expression through STAT3-FoxM1 axis | • ↑Cell proliferation, invasion, and sphere formation in vitro and tumor growth in vivo • Positive correlation with tumor grade (Grade III and IV) |
ST3GAL1 [79] | ↑ | GBM | ST3GAL1 APC/C-Cdh1/FoxM1 | ST3GAL1 indirectly controls FoxM1 protein degradation by the APC/C-Cdh1 complex | • ↑Cell proliferation, invasion • Correlated with patient survival, higher tumor grade, and volume |
ALKBH5 [61] | ↑ | GBM | ALKBH5/FOXM1 | ALKBH5 demethylates FOXM1 nascent transcripts, leading to enhanced FOXM1 expression | • ↑ Proliferation and tumorigenesis • Negatively correlated with patient prognosis • ALKBH5 is associated with GSC Self-Renewal |
MTDH [80] | ↑ | GBM | MTDH/ FOXM1 | MTDH stabilizes FOXM1 by inhibiting its ubiquitination MTDH enhances FOXM1 transcriptional activity | • ↑Cell cycle progression, angiogenesis, and invasion |
MTDH [81] | ↑ | Glioma(subtype not mentioned) | MTDH/FOXM1/MYBL2 | – | • ↑Cell proliferation, migration, and invasion |
SGO2 [82] | ↑ | GBM | SGO2/ FOXM1 | – | • Positively correlates with WHO grading and poor survival of high-grade gliomas • ↑Cell proliferation and migration |
AVIL [83] | ↑ | GBM | AVIL/FOXM1 | AVIL regulates FOXM1 stability through regulating F-actin dynamics | • ↑Proliferation rates and increased migration |
Methionine [84] | ↑ | Glioma-initiating cells | Methionine/SREBF2/FOXM1 | FOXM1 was down-regulated with SREBF2 by methionine depletion | • ↑ Self-renewal and pluripotency • ↑Cell proliferation • ↓Cell death • FOXM1 is associated with cholesterol metabolism |
lncRNA- HULC [85] | ↑ | GBM and GSCs | HULC/FOXM1/AGR2/HIF-1α | HULC stabilizes the FOXM1 protein through ubiquitination | • ↑ Stemness, proliferation, and glycolysis • ↓Apoptosis |
CircPIK3C2A [86] | ↑ | GBM | CircPIK3C2A/miR-877-5p/FOXM1 | CircPIK3C2A upregulates FOXM1by sponging miR-877-5p | • ↑ Proliferation, migration, and invasion • ↑Growth of xenografted tumors in vivo |
lncRNA MYCNOS [87] | ↑ | GBM | MYCNOS/miR-216b/FOXM1 | MYCNOS upregulates FOXM1by sponging miR-216b | • ↑Proliferation |
miR-216b [88] | ↓ | GBM | miR-216b/FOXM1 | miR-216b targets 3′ UTR of FOXM1 | • ↑Proliferation, migration, and invasion • ↑Tumourigenesis in vivo |
miR-325-3p [89] | ↓ | Glioma | miR-325-3p/FOXM1 | miR-325-3p targets 3′ UTR of FOXM1 | • ↑Viability and proliferation growth |
miR-320 [90] | ↓ | Glioma | miR-320/FOXM1/SIRT1 | miR-320 targets 3′ UTR of FOXM1 | • ↑Radioresistance caused by Sirt1 upregulation |
miR-370-3p [91] | ↓ | GBM | miR-370-3p/FOXM1 | miR-370-3p targets 3′ UTR of FOXM1 | • Temozolomide sensitivity |
miR-525-5p [53] | ↓ | Glioma | miR-525-5p/STAT1/FOXM1 | miR-525-5p targets 3′ UTR of STAT1 | • Development of glioma both in vitro and in vivo • Proliferation, migration, invasion, and EMT upon miR-525-5p downregulation |
circBFAR [92] | ↑ | GBM | miR-548b/FOXM1 | circBFAR sponges miR-548b | • ↑Proliferative and invasive |
circCCDC66 [93] | ↑ | Grade III-IV | circCCDC66/miR-320ab/FoxM1 | Sponging miR-320ab by circCCDC66/ Targeting 3′ UTR of FOXM1 by miR-320ab | • ↑Proliferation, migration, and invasion |
Downstream targets of FOXM1 | |||||
Anxa1 [24] | ↑ | GBM | FOXM1/Anxa1 | Enhance the Anxa1 promoter activity | • ↑Proliferation, migration, and angiogenesis |
STAT3 [26] | ↑ | GBM | FOXM1/STAT3 | – | • Radiation-induced activation of STAT3 and FOXM1 induction is mutually co-regulated • FOXM1/STAT3 interacts and co-localize following radiation therapy |
CDC20 [38] | ↑ | GBM | FOXM1/CDC20/p21CIP1/WAF1 | Binds to the promoter region of CDC20 | • ↑Proliferation and survival of TICs |
MYBL2 [41] | ↑ | Grade III-IV | Akt/ FOXM1/MYBL2 | – | • Linked with poor outcome and grade • ↑Tumor progression: migration, invasion, and EMT • ↓Cell apoptosis • MYBL2 is a radiosensibility biomarker of glioma |
ADAM17 [57] | ↑ | GBM | FOXM1/ADAM17/EGFR/Akt | Binds to the ADAM17 promoter region | • ADAM17 forms a positive loop by increasing the activity of EGFR/Akt axis • ADAM17 promotes MES transition in GBM and tumor malignancy in vivo |
UBE2C [94] | ↑ | Grade I-IV | FOXM1/UBE2C | Binds to and activates the UBE2C promoter | • ↑Proliferation • UBE2C inhibition causes autophagy |
Rad51 [95] | ↑ | GBM | FOXM1/Rad51 | Binds to Rad51 promoter | • ↑Chemoresistance • Negative predictor of prognosis |
RFC5 [96] | ↑ | Grade I-IV | FOXM1/RFC5 | Interacts with RFC5 promoter | • FOXM1 confers TMZ resistance in glioma cells independent of MGMT activation |
BUB1B [97] | ↑ | GBM | FOXM1/BUB1B | Binds to BUB1B promoter | • Poor prognosis in GBM • ↑Proliferation • BUB1B-mediated radioresistance is essential for GBM recurrence |
Sox2 [98] | ↑ | GBM | FOXM1/Sox2 | Binds to Sox2 promoter | • Sox2 is upregulated in radioresistant cells • FOXM1 knockdown sensitizes GBM cells to radiation • Correlates with glioma grades and predicts poor patient survival |
MMP-2 [99] | ↑ | GBM | FOXM1/MMP-2 | Binds to MMP-2 promoter | • ↑Invasion |
VEGF [56] | ↑ | GBM | FOXM1/VEGF | Binds to VEGF promoter | • ↑Growth and angiogenesis |
Sirt1 [100] | ↑ | Grade III-IV | FOXM1/SIRT1 | Binds to the promoter region of SIRT1 | - |
ASPM [101] | ↑ | GBM | FOXM1/ASPM | Binds to the promoter region of ASPM | • ↑Proliferation, migration, and invasion • Predicts poor prognosis in gliomas |
NUF2 [102] | ↑ | GBM | FOXM1/NUF2 | Binds to NUF2 promoter | • ↑Proliferation and autophagy • ↓ Apoptosis • ↑TMZ-resistant |
TRIP13 [103] | ↑ | Grade I-IV | FOXM1/TRIP13 | – | • TRIP13 is co-expressed with FOXM1 |