Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression
Abstract
:1. Introduction
2. Canonical Hypoxia Signaling
2.1. HIF Transcription Factors: The Central Regulator of Oxygen Homeostasis
2.2. Prolyl Hydroxylation: The Adaptive Mediator of HIFs
2.3. pVHL: The Proteolysis Modulator of HIFs
3. 2-Oxoglutarate-Dependent Enzymes in Gene Regulation and Cancer Progression
3.1. Proline and Asparagine Hydroxylases
3.2. DNA/RNA-Modifying Enzymes
3.3. JmjC Domain-containing Enzymes
4. Therapeutic Implications on Targeting Hypoxia and Oxygen Sensing Pathways in Cancer
4.1. Inhibitors for HIF-1α
4.2. Inhibitors for HIF-2α
4.3. Inhibitors for 2-OG-Dependent Enzymes
4.4. Targeting Proteins Using pVHL-Based PROTACs
5. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
2-OG dependent | 2-oxoglutarate-dependent |
5caC | 5-carboxylcytosine |
5fC | 5-formylcytosine |
5hmC | 5-hydroxymethycytosine |
5mC | 5-methylcytosine |
ALDH2 | Aldehyde Dehydrogenase 2 |
AML | Acute Myeloid Leukemia |
ARNT | Aryl hydrocarbon Receptor Nuclear Translocator |
Card9 | Caspase Recruitment Domain Family Member 9 |
CBP | CREB-Binding Protein |
ccRCC | Clear Cell Renal Cell Carcinoma |
CEP68 | Centrosomal Protein 68 |
CERKL | Ceramide Kinase-like Protein |
CODD | C-terminal Oxygen-dependent Degradation Domain |
CRBN | Cereblon |
DEACM | Diethylamino Coumarin |
DMNB | 4,5-dimethoxy-2-nitrobenzyl |
EMT | Epithelial-Mesenchymal Transition |
EPOR | Erythropoietin Receptor |
FIH | Factor Inhibiting HIF |
FLNA | Actin Cross-linker Filamin A |
FTO | Fat mass and Obesity-associated protein |
HIF | Hypoxia-Inducible Factor |
HRE | Hypoxia-Responsive Elements |
IP3R3 | Inositol-1,4,5-triphosphate Receptor type 3 |
IPAS | Inhibitory PAS protein domain |
JmjC | Jumonji C |
KDM/JMJD | Histone Lysine Demethylase |
LSD | Lysine Specific Demethylase |
m6A | N6-Methyladenosine |
NDRG3 | N-Myc Downstream-Regulated Gene 3 |
NLR | NOD-Like Receptor |
NODD | N-terminal Oxygen-dependent Degradation Domain |
NPOM | 6-nitropiperonyloxymethyl |
ODD | Oxygen-dependent Degradation Domain |
PGC-1α | Proliferator-activated receptor-Gamma Coactivator-1 alpha |
PHD | Prolyl Hydroxylase |
PROTACs | PROteolysis-TArgeting Chimeras |
pVHL | Von Hippel-Lindau protein |
TBK1 | TANK Binding Kinase 1 |
TDG | Thymine–DNA Glycosylase |
TME | Tumor Micro-Environment |
TET | Ten Eleven Translocation |
Ub | Ubiquitylation |
UPS | Ubiquitin-Proteasome System |
VEGF | Vascular Endothelial Growth Factor |
ZHX2 | Zinc fingers and Homeoboxes 2 |
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Compound | Target | Cancer Type | Mechanism/Outcomes | Reference |
---|---|---|---|---|
Apigenin | HIF-1 | Ovarian cancer | Targets PI3K/AKT signaling and downregulates HIF-1 and VEGF expression | [165,166] |
SU5416 | HIF-1 | Acute myeloid leukemia, ovarian cancer, anaplastic thyroid carcinoma | Inhibits ability of HIF-1 to bind DNA; decreases VEGF and HIF-1α expression; downregulates VEGF, PI3K, AKT, and p70S6K1 | [167,168,169] |
PX-478 | HIF-1 | Prostate, breast, colon, and pancreatic cancer | Modulates HIF-1α deubiquitylation, inhibits HIF-1α transcription and translation | [170] |
BAY 87-2243 | HIF-1, HIF-2 | Non-small cell lung cancer | Prevents accumulation of HIF-1α and HIF-2α | [171] |
Moracin O and moracin P | HIF-1 | Hepatocellular carcinoma | Inhibits HIF-1 activation | [172] |
YC-1 | HIF-1 | Prostate cancer | Activates soluble guanylyl cyclase, induces HIF-1 degradation, targets PI3K/Akt/mTOR and NF-κB signaling | [173] |
Cardamonin | HIF-1 | Triple-negative breast cancer | Inhibits the mTOR/p70S6K pathway and HIF-1α expression | [174] |
PT-2399 | HIF-2 | Clear cell renal cell carcinoma | Inhibits HIF-2α-ARNT dimerization | [175,177,178] |
PT-2385 | HIF-2 | Clear cell renal cell carcinoma, lung cancer cell xenograft, hepatocellular carcinoma | Reduces the levels of tumor-induced circulating VEGFA, represses HIF-2α-related Stat-3/Akt/Erk signaling | [175,177,178,180,181] |
TC-S 7009 | HIF-2 | Hepatoma | Prevents DNA binding, heterodimerization, and the transcription activation of HIF-2α by inducing allosteric conformational changes in PAS-B β-sheets | [177,182] |
Compound-76 | HIF-2 | Breast cancer | Inhibits HIF-2α translation by promoting interaction of IRP1 and HIF-2α mRNA, represses chemoresistance and stem-ness | [183,184] |
Vorinostat/SAHA | JMJD2 | Cutaneous T cell lymphoma | Inhibits JMJD2 | [185] |
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Yang, G.; Shi, R.; Zhang, Q. Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression. Int. J. Mol. Sci. 2020, 21, 8162. https://doi.org/10.3390/ijms21218162
Yang G, Shi R, Zhang Q. Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression. International Journal of Molecular Sciences. 2020; 21(21):8162. https://doi.org/10.3390/ijms21218162
Chicago/Turabian StyleYang, Guang, Rachel Shi, and Qing Zhang. 2020. "Hypoxia and Oxygen-Sensing Signaling in Gene Regulation and Cancer Progression" International Journal of Molecular Sciences 21, no. 21: 8162. https://doi.org/10.3390/ijms21218162