Hypoxia induces H19 expression through direct and indirect Hif-1α activity, promoting oncogenic effects in glioblastoma.
H19 expression is elevated in many human tumors including glioblastomas, suggesting an oncogenic role for the long noncoding RNA; yet the upregulation of H19 in glioblastomas remains unclear. Here we report that hypoxia significantly stimulated H19 expression in glioblastoma cell lines, which was related to hypoxia-inducible factors 1α (Hif-1α). Hif-1α promoted H19 expression in U87 and U251 cells. Meanwhile PTEN is an advantageous factor to affect H19 expression, through attenuating Hif-1α stability. Hif-1α also positively correlates with H19 in human glioblastoma samples depending on PTEN status. ChIP and luciferase reporter assays showed that Hif-1α induced H19 transcription through directly binding to the H19 promoter. Furthermore, Hif-1α upregulated specific protein 1 (SP1) expression in glioblastomas cells in vitro and in vivo, and SP1 also strongly interacted with the H19 promoter to promote H19 expression under hypoxia. We also showed that H19 acts as a molecular sponge that binds miR-181d, relieving inhibition of β-catenin expression. Therefore, H19 participates in hypoxia-driven migration and invasion in glioblastoma cells. In summary, our results uncover the mechanisms that stimulate H19 expression under hypoxia to promote malignant effects in glioblastomas and suggest H19 might be a promising therapeutic target.
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Weining
W
Wu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Qi
Q
Hu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Er
E
Nie
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Tianfu
T
Yu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Youzhi
Y
Wu
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Tongle
T
Zhi
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Kuan
K
Jiang
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Feng
F
Shen
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Yingyi
Y
Wang
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Junxia
J
Zhang
Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210000, China.
Yongping
Y
You
D000818:Animals; D014408:Biomarkers, Tumor; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D015870:Gene Expression; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D000860:Hypoxia / Q000235:genetics* / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011379:Prognosis; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
D014408:Biomarkers, Tumor; C094335:H19 long non-coding RNA; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C000608460:MIRN-181 microRNA, human; D035683:MicroRNAs; D062085:RNA, Long Noncoding; D016329:Sp1 Transcription Factor; D051176:beta Catenin; D051059:PTEN Phosphohydrolase