Hif-1α and Hif-2α differentially regulate Notch signaling through competitive interaction with the intracellular domain of Notch receptors in glioma stem cells.
Hypoxia contributes to GSC expansion principally through Hif-1α and Hif-2α, but how these two factors work together has not been completely understood. We show that hypoxia promoted proliferation, self-renewal and inhibited the conversion of GSCs into INP-like cells through activating Notch signaling. Further data suggested that Hif-2α interacted with NICD and repressed the activity of Notch signaling, in contrast to the role of Hif-1α in Notch signaling. Together, our findings suggest that Hif-1α and Hif-2α competitively bind to NICD and dynamically regulate the activation of Notch signaling in GSCs likely depending on different oxygen tensions, providing improved therapeutic opportunities for malignant gliomas.
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
Yi-Yang
YY
Hu
Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
Luo-An
LA
Fu
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China; Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
San-Zhong
SZ
Li
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
Yan
Y
Chen
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
Jun-Chang
JC
Li
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
Jun
J
Han
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
Liang
L
Liang
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China; Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
Liang
L
Li
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China; Department of Neurosurgery, Xijing Hospital, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China.
Chen-Chen
CC
Ji
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China. Electronic address: zhengminhua@gmail.com.
Min-Hua
MH
Zheng
State Key Laboratory of Cancer Biology, Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xi'an 710032, China. Electronic address: huahan@fmmu.edu.cn.
Hua
H
Han
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D019556:COS Cells; D048708:Cell Growth Processes / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D002522:Chlorocebus aethiops; D005910:Glioma / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000378:metabolism*; D015533:Transcriptional Activation; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051880:Receptors, Notch; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human
Glioma stem cells; Hif-1α; Hif-2α; Hypoxia; Notch