title: MiR-215 Is Induced Post-transcriptionally via HIF-Drosha Complex and Mediates Glioma-Initiating Cell Adaptation to Hypoxia by Targeting KDM1B.
abstract: The hypoxic tumor microenvironment serves as a niche for maintaining the glioma-initiating cells (GICs) that are critical for glioblastoma (GBM) occurrence and recurrence. Here, we report that hypoxia-induced miR-215 is vital for reprograming GICs to fit the hypoxic microenvironment via suppressing the expression of an epigenetic regulator KDM1B and modulating activities of multiple pathways. Interestingly, biogenesis of miR-215 and several miRNAs is accelerated post-transcriptionally by hypoxia-inducible factors (HIFs) through HIF-Drosha interaction. Moreover, miR-215 expression correlates inversely with KDM1B while correlating positively with HIF1α and GBM progression in patients. These findings reveal a direct role of HIF in regulating miRNA biogenesis and consequently activating the miR-215-KDM1B-mediated signaling required for GIC adaptation to hypoxia.
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Tao
authors.initials: T
authors.lastname: Sun
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Zhengxin
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Shuai
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Lifeng
authors.initials: L
authors.lastname: Yuan
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Tingyu
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Hai-Ri
authors.initials: HR
authors.lastname: Li
authors.affiliation: Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Pingping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Department of Anatomy, Mudanjiang Medical College, Mudanjiang, Heilongjiang Province 157011, China.
authors.forename: Yukuan
authors.initials: Y
authors.lastname: Feng
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Qinhong
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Roger E
authors.initials: RE
authors.lastname: McLendon
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Allan H
authors.initials: AH
authors.lastname: Friedman
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Stephen T
authors.initials: ST
authors.lastname: Keir
authors.affiliation: The Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Darell D
authors.initials: DD
authors.lastname: Bigner
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Jeff
authors.initials: J
authors.lastname: Rathmell
authors.affiliation: Department of Cellular & Molecular Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Xiang-Dong
authors.initials: XD
authors.lastname: Fu
authors.affiliation: Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Qi-Jing
authors.initials: QJ
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province 210029, China.
authors.forename: Huibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA. Electronic address: xiao.fan.wang@duke.edu.
authors.forename: Xiao-Fan
authors.initials: XF
authors.lastname: Wang
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000235:genetics / Q000473:pathology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics*; D005910:Glioma / Q000235:genetics*; D006801:Humans; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009364:Neoplasm Recurrence, Local / Q000235:genetics; D010089:Oxidoreductases, N-Demethylating / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics*
chemical_list: C553667:MIRN215 microRNA, human; C577160:MIRN215 microRNA, mouse; D035683:MicroRNAs; D010089:Oxidoreductases, N-Demethylating; C544113:kdm1b protein, mouse