CREBRF is a potent tumor suppressor of glioblastoma by blocking hypoxia-induced autophagy via the CREB3/ATG5 pathway.
Hypoxia induces protective autophagy in advanced glioblastoma cells, and targeting this process may improve the outcome for glioblastoma patients. Recent studies have suggested that the autophagic process is upregulated in glioblastoma cells in response to extensive hypoxia. Here, we describe a novel tumor suppressor in glioblastoma cells, whereby hypoxia downregulated CREBRF expression and acts as a potent inhibitor of autophagy in glioblastoma cells via the CREB3/ATG5 pathway. Our results demonstrate that CREBRF expression negatively correlates with autophagic and HIF-1α levels in different grade gliomas. Given that CREBRF is a negative regulator of CREB3, CREB3 knockdown also repressed hypoxia-induced autophagy in glioblastoma cells in vitro. Collectively, our findings provide new insight into the molecular mechanisms underlying hypoxia-induced glioblastoma cell autophagy and indicate that the hypoxia/CREBRF/CREB3/ATG5 pathway plays a central role in malignant glioma progression.
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Hao
H
Xue
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Jinsen
J
Zhang
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Xing
X
Guo
Department of Biomedicine, University of Bergen, 5009 Bergen, Norway.
Jian
J
Wang
Department of Cardiology, Shandong Provincial Hospital of Shandong University, Jinan, Shandong 250021, P.R. China.
Jiangbing
J
Li
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Xiao
X
Gao
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Xiaofan
X
Guo
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Tong
T
Li
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Shugang
S
Xu
Brain Science Research Institute, Shandong University, Jinan, Shandong 250012, P.R. China.
Ping
P
Zhang
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Qinglin
Q
Liu
Department of Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong 250012, P.R. China.
Gang
G
Li
D001343:Autophagy / Q000235:genetics / Q000502:physiology; D000071187:Autophagy-Related Protein 5 / Q000235:genetics / Q000378:metabolism*; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia / Q000502:physiology*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
C502778:ATG5 protein, human; D000071187:Autophagy-Related Protein 5; C107941:CREB3 protein, human; C000617553:CREB3 regulatory factor, human; D017362:Cyclic AMP Response Element-Binding Protein; D025521:Tumor Suppressor Proteins