HIF1α regulates glioma chemosensitivity through the transformation between differentiation and dedifferentiation in various oxygen levels

Abstract

Chemotherapy plays a significant role in glioma treatment; however, it has limited effectiveness in extending the life expectancies of glioma patients. Traditional studies have attributed this lack of efficacy to glioma stem cells (GSCs) and their high resistance to chemotherapy, and hypoxia worsens this issue. In contrast, hyperoxia effectively alleviates hypoxia in glioma and sensitizes glioma cells to chemotherapy. In a summary of traditional studies, the majority of researchers overlooked the influence of hypoxia on differentiated cells because they only focused on the maintenance of GSCs stemness, which thus resulted in chemoresistance. Because of this background, we hypothesized that GSCs may be induced through dedifferentiation under hypoxic conditions, and hypoxia maintains GSCs stemness, which thus leads to resistance to chemotherapy. In contrast, hyperoxia inhibits the dedifferentiation process and promotes GSCs differentiation, which increases the sensitization of glioma cells to chemotherapy. Hypoxia-inducible factor-1α (HIF1α) contributes substantially to the stemness maintenance of GSCs and resistance of glioma to chemotherapy; thus, we investigated whether HIF1α regulates the resistance or sensitization of glioma cells to chemotherapy in different oxygen levels. It highlights a novel viewpoint on glioma chemosensitivity from the transformation between dedifferentiation and differentiation in different oxygen levels.

De-novo purine biosynthesis is a major driver of chemoresistance in glioblastoma

“…Previous reporting demonstrated that Hypoxia-inducible factors (HIFs) are critical for maintenance of the BTIC niche and that HIF-1α (HIF1A) can directly modulate EZH2 expression via promoter binding 30,31 . We have shown that TMZ therapy increases the BTIC frequency in a HIF dependent manner 20,32 . Now we show that the TMZ-mediated increase in HIF1A is specific to the CD133+ BTIC compartment…”

“…A canonical driver of context-dependent epigenetic plasticity is the Polycomb Repressor Complex (PRC) and its catalytic subunit Enhancer of Zeste Homologue 2 (EZH2). The PRC2/EZH2 complex not only required for different neurodevelopmental processes but also associated with disease pathogenesis including GBM [13][14][15][16][17][18][19][20] . Tumor cells can also adapt to treatment metabolically by rapidly altering core metabolic pathway activity 21,22 .…”

Long-Term Deleterious Effects of Short-term Hyperoxia on Cancer Progression—Is Brain-Derived Neurotrophic Factor an Important Mediator? An Experimental Study

“…We also identified that HIF-1α can be upregulated in TNBC cells after short-term hyperoxia exposure. There is a vast body of literature demonstrating that HIF-1α increases in hypoxia while in hyperoxic regimens usually decreases [17,18]. However, in skeletal muscle cells under high oxygen concentrations (42%), the amount of HSP90-HIF-1α complex is increased and suggests that HSP90 stabilizes cytoplasmic HIF-1α under high oxygen levels [39].…”

“…In cancer BDNF has been shown to play a role in proliferation, invasion and metastasis in central nervous system, mammary, ovarian, pancreatic and uterine neoplasms [13][14][15][16]. BDNF promotes angiogenesis by increasing VEGFR expression through HIF-1α [17].Small levels of ROS will induce insufficient BDNF expression, while high levels of ROS will induce extended BDNF stimulation leading to epithelial mesenchymal transition (EMT) and angiogenesis. EMT induces new cancer stem cell formation that may be responsible for cancer recurrence.…”

“…In cancer BDNF has been shown to play a role in proliferation, invasion and metastasis in central nervous system, mammary, ovarian, pancreatic and uterine neoplasms [13][14][15][16]. BDNF promotes angiogenesis by increasing VEGFR expression through HIF-1α [17].…”