Table 3 Upstream regulators and targets of FOXO1 in glioma
Name | Cancer type | Axis | Action | Role of FOXO1 | Highlights |
|---|---|---|---|---|---|
Upstream regulators of FOXO1 | |||||
 Sirt1 [153] | GBM | AKT-ERK/SIRT1/FOXO1 | – | TS | • ↓Proliferation and migration |
 TGF-β/Smad [148] | GBM | TGF-β/Smad/FOXO1/p21Cip1 | Binding to FOXO1 and forming a complex | TS | • SMAD3-SMAD4-FOXO1 complex can inhibit cell proliferation by inducing p21Cip1 |
 lncRNA-DANCR [154] | GBM | IGF2BP2/DANCR/FOXO1/PID1 | DANCR elevated the ubiquitination level of FOXO1 | TS | • IGF2BP2 expression is increased in GBMs, leading to lncRNA DANCR overexpression • DANCR causes etoposide resistance via inhibiting FOXO1 |
 miR-5188 [138] | Glioma | SP1-activated PI3K/AKT/c-JUN/miR-5188/ FOXO1 | Targets FOXO1 3′ UTR | TS | • miR-5188 promoted cell proliferation, the G1/S transition of the cell cycle, migration, and invasion in glioma • c-JUN binds to the promoter region of miR-5188 • c-JUN expression is increased upon PI3K/Akt signaling activation mediated by SP-1 |
 SOX2/miR-486–5p [150] | GBM | Sox2/miR-486–5p/FOXO1 | miR-486–5p targets FOXO1 3′ UTR | TS | • Sox2 induces miR-486–5p • miR-486–5p regulates GBM cell survival • Suppression of miR-486–5p in vivo inhibits the growth of GBM and sensitizes it to radiation |
 miR-28-5p [155] | GBM | miR-28-5p/ FOXO1/CyclinD1 | Targets FOXO1 3′ UTR | TS | • ↑Growth |
 miR-374a [156] | Glioma | miR-374a/FOXO1/Bim and Noxa | Targets FOXO1 3′ UTR | TS | • ↓Mitochondrial apoptosis • ↑Resistance to etoposide |
Glioma | miR-135a/FOXO1 | Targets FOXO1 3′ UTR | Oncogene | • miR-135a inhibits cell proliferation and invasion by targeting FOXO1 | |
 lncRNA specific 5 (GAS5) [158] | Glioma stem cells (GSCs) | GAS5/miR-196a-5p/FOXO1/PID1 and MIIP | *miR-196a-5p targets FOXO1 3′ UTR *GAS5 downregulates miR-196a-5p | TS | • GAS5 and FOXO1 increase the expression of each other by forming a loop • ↓Migration, invasion, and proliferation • ↑Apoptosis |
 circGFRA1 [151] | Glioma | circGFRA1/ miR-99a/AKT/FOXO1 | circGFRA1 downregulates miR-99a miR-99a targets FOXO1 3′ UTR | TS | • ↑Cell proliferation and migration |
 miR-637 [159] | High-grade glioma | miR-637/Akt1/FOXO1 | miR-637 targets Akt1 3′UTR and Akt1 inhibits FOXO1 | TS | • miR-637 is downregulated in gliomas • ↓Proliferation, invasion, and migration |
 miR-21 [160] | GBM | miR-21/FOXO1 | Targets FOXO1 3′ UTR | TS | • ↑Proliferation • ↓Apoptosis |
 miR-183/96/182 [161] | Glioma | miR-183-96-182/FOXO1 | Targets FOXO1 3′ UTR | TS | • ↑Cell survival via downregulating FOXO1 • ↓ROS production • Sensitizes cells to chemotherapy |
 mTORC2 [140] | GBM | mTORC2/ FOXO1/miR-34c/c-MYC | Regulates FoxO acetylation through Class IIa HDACs, independent of Akt | TS | • Combined inhibition of PI3K/Akt and mTORC2 suppresses acetylated FoxO/c-Myc signaling and promotes tumor cell death • Contributes to cell survival and Warburg’s effect |
 LITAF [162] | Glioma | LITAF/FOXO1/Bim, TRAIL, and FASLG | Increases FOXO1 expression [The exact mechanism was not mentioned] | TS | • LITAF expression did not affect proliferation and apoptosis, however, it promoted radiosensitivity of U251 and U373 cells via the FOXO1 pathway |
 KLF4 [163] | High-grade glioma | KLF4/FOXO1 | KLF4 binds to FOXO1 promoter and inhibits its transcription | TS | • FOXO1 inhibits glioma cells invasion and growth • KLF4 expression inversely correlated with FOXO1 expression |
 RFP [164] | GBM | RFP/HDAC1/FOXO1 | Inhibits FOXO1 mediated by HDAC1 | TS | • RFP knockdown causes oxidative stress, and apoptosis and increases TMZ chemosensitivity by histone modification |
 TRIM47 [133] | Low-grade and high-grade gliomas | TRIM47/FOXO1 | Degrades FOXO1 through ubiquitination | TS | • TRIM47 promotes the proliferation, migration, and invasion of glioma cells through FOXO1 ubiquitination |
 Quinolinate [165] | GBM | Metabolite of tryptophan | Leads to phosphorylation and degradation of Foxo1 | TS | • Modulates M2 macrophage polarization • ↑Immune suppression |
Downstream targets of FoxO1 | |||||
 Cyclin D kinase 1 (CDK1( [146] | Glioma | FOXO1/CDK1 | Phosphorylates FOXO1 | TS | • ↑G2/M phase proportion • ↓Cell proliferation • ↑Apoptosis |
 p21Cip1 [148] | GBM | TGF-β/Smad/FOXO1/p21Cip1 | FOXO1 binds to p21Cip1 promoter | TS | • FOXO and Smad proteins rapidly and specifically bind to contiguous sites on the p21Cip1 promoter and mediate p21Cip1 activation • FOXG1 suppresses p21Cip1 induction |
 PID1 [154] | GBM | IGF2BP2/DANCR/FOXO1/PID1 | FOXO1 binds to PID1 promoter | TS | • FOXO1 decreases etoposide resistance by promoting PID1 expression |
 OCT4 [137] | GBM | FOXO1/OCT4 | Binding to OCT4 promoter region | Oncogene | • FOXO1 increases the expression of stem cell markers such as OCT4 |
 SOX2 [136] | GBM stem cells | FOXO1/SOX2 | Binding to Sox2 promoter region | Oncogene | • FOXO1 knockdown marginally reduces the expression of stemness markers and cell death after γIR or γIR/PI-103 combination treatment |
 RFC2 [152] | GBM radioresistant cells | FOXO1/ RFC2 | Binding to RFC2 promoter region | Oncogene | • FOXO1 positively regulates the expression of RFC2 in TMZ drug-resistant glioma cells • ↑Cell proliferation and colony formation • ↓Apoptosis |