Table 5 Upstream regulators and targets of FOXO3 in glioma
Name | Cancer type | Axis | Role of FOXO3 in the study | Action | Highlights |
|---|---|---|---|---|---|
CHAF1A [191] | GBM | CHAF1A/AKT/FOXO3a/Bim | TS | CHAF1A phosphorylates Akt and FOXO3a and decrease its nuclear localization | • ↓Survival and apoptosis • ↑Proliferation |
IGF1 [189] | GSCs | IGF1/AKT/FOXO3a | Oncogene in radioresistant tumor spheres/TS in non-radiated cells | IGF1 induces FOXO3a expression in the resting state and nuclear localization of FOXO3a in radioresistant cell lines | • In the resting state, IGF1 downregulates Akt and FOXO3a activation, which results in slower proliferation and enhanced self-renewal • After acute radiation, IGF1 promote a rapid shift from a latent state toward activation of Akt survival signaling, resulting in GSCs radioprotection |
GGCT [182] | GBM cells | AMPK/FOXO3a/p21 | TS | GGCT inhibits AMPK, and AMPK phosphorylates FOXO3a at Ser413 | • ↑Growth |
Cathepsin B and uPAR [184] | glioma xenograft cell lines | CathB-uPAR/EGFR/Akt-ERK/FOXO3a/p27 | TS | CathB-uPAR decreases the activity of FOXO3a | • ↑Cell proliferation |
CLK2 [188] | GSCs | CLK2/AKT/FOXO3a | TS | CLK2 phosphorylates Akt and FOXO3a and decrease its nuclear localization | • ↑Proliferation and viability via inhibiting cell cycle arrest • ↓Survival and outcome |
SPHK1 [190] | Glioma | SPHK1/Akt/FOXO3a/Bim | TS | SPHK1 phosphorylates Akt and FOXO3a and decrease its nuclear localization | • ↓Apoptosis |
FOXM1B [192] | GBM | FOXM1B/NEDD4-1/PTEN/Akt/FOXO3a | TS | PTEN reduction and Akt activation | • ↑Malignant transformation • ↑Growth |
FOXG1/SOX2 [221] | GBM stem cells | FOXG1/SOX2/FOXO3 | TS | Transcriptional repression | • FOXG1 reduces BMP-induced astrocyte differentiation • SOX2 is necessary for constant proliferation but FOXG1 is not |
PINK1 [199] | GBM | PINK1/FOXO3a/ROS/HIF-1 | TS | PINK1 inhibits FOXO3a phosphorylation | • ↓Viability and growth |
DNA-PKcs [201] | GBM | DNA-PKcs/FOXO3a | NA | NA | • DNA-PKcs is activated under nutrient starvation and activates Akt, MST1, and FOXO3a |
MST1 [208] | Glioma | MST1/FOXO3a/SIRT6 | TS | MST1 translocated FOXO3a to the nucleus | • ↓Cell viability and colony formation and induces cell apoptosis |
PTEN [228] | GBM | PTEN/Akt/ FOXO3a/LIFRβ/STAT3 | TS | PTEN loss and consequent Akt activation inhibit FOXO3-dependent LIFRβ gene expression in astrocytes | • PTEN loss correlates tightly with low levels of LIFRβ expression and inactivation of STAT3 |
Circ-DONSON [229] | Glioma | Circ-DONSON/FOXO3a | TS | Downregulates FOXO3a | • Circ-DONSON was correlated with lymph node, distant metastasis, and poor prognosis of glioma patients • ↑Cell proliferation and migration |
miR-27a [224] | GBM | miR-27a/FOXO3a | TS | Targets 3′UTR of FOXO3a | • ↑Proliferation and growth |
miR-155 [230] | Murine glioma and CD8+ cells | miR-155/FOXO3a/Akt and Stat5 | NA | Targets 3′UTR of FOXO3a | • miR-155 loss induced glioma progression, reduced the CD-8+ T Cells • FoxO3a negatively regulates Akt and STAT5 expression |
miR-155 [226] | Glioma | miR-155/FOXO3a | TS | Targets 3′UTR of FOXO3a | • ↑Proliferation by inhibiting apoptosis • ↑Migration and invasion |
miR‑370 [214] | Astrocytoma and GBM | miR‑370/β-catenin and FOXO3a | TS | Probably targets 3′UTR of FOXO3a | • miR-370 mimics leads to accumulation of FOXO3a in the nuclei astrocytoma cells |
miR-93 [225] | Glioma | miR-93/ PTEN, PHLPP2 and FOXO3 | TS | Targets 3′UTR of FOXO3a | • ↑Proliferation and cell cycle progression through suppressing PTEN, PHLPP2 or FOXO3 |
miR-184 [218] | Glioma | miR-184/FOXO3a | TS | Targets 3′UTR of FOXO3a | • ↑Proliferation |
miR-10b [223] | GBM | miR-10b/FOXO3a | TS | NA | • ↑Angiogenesis • Poorer patient survival |
miR-27a-3p [231] | GBM | miR-27a-3p/FTO/FOXO3a | TS | miR-27a-3p targets 3′UTR of FTO FTO interacts with FOXO3 to increase its expression | • ↑Proliferation, invasion, migration, and tumor growth |
Downstream targets | |||||
 BNIP3 [204] | Glioma | TMZ/ROS/FOXO3a/BNIP3 | Oncogene | ROS produced by TMZ induces expression of FOXO3a, which causes BNIP3 overexpression | • ↑TMZ-induced mitophagy • Protects cells against temozolomide-induced DNA double strand breaks |
 SIRT6 [207] | GBM | FOXO3a/SIRT6 | TS | FOXO3a positively correlates with SIRT6 expression | • FKHRL1/FOXO3a low expression predicts poor prognosis of patients with glioma • ↓Warburg effect and cell proliferation • FOXO3a negatively correlated with glycolytic genes including glut4, glut1, and LDHA |
Glioma cells resistant to TMZ | FOXO3a/MMP9/β-catenin | Oncogene | FOXO3a induces β-catenin via increasing MMP-9 expression | • Poor prognosis | |
 Lnc-TALC [227] | GBM | Lnc-TALC/miR-20b-3p/c-Met/MGMT | TS | FOXO3 binds to the promoter region of lnc-TALC in TMZ sensitive cells In TMZ resistant cells degradation of FOXO3a followed by c-Met/Akt axis in cytoplasm is observed | • Less aggregated FOXO3 was in the nucleus of TMZ-resistant GBM cells than in parental cells • Knockdown of AKT in TMZ-resistant cells decreased lnc-TALC but increased the level and nuclear translocation of FOXO3 |