The Long Non-coding RNA HIF1A-AS2 Facilitates the Maintenance of Mesenchymal Glioblastoma Stem-like Cells in Hypoxic Niches.
Long non-coding RNAs (lncRNAs) have an undefined role in the pathobiology of glioblastoma multiforme (GBM). These tumors are genetically and phenotypically heterogeneous with transcriptome subtype-specific GBM stem-like cells (GSCs) that adapt to the brain tumor microenvironment, including hypoxic niches. We identified hypoxia-inducible factor 1 alpha-antisense RNA 2 (HIF1A-AS2) as a subtype-specific hypoxia-inducible lncRNA, upregulated in mesenchymal GSCs. Its deregulation affects GSC growth, self-renewal, and hypoxia-dependent molecular reprogramming. Among the HIF1A-AS2 interactome, IGF2BP2 and DHX9 were identified as direct partners. This association was needed for maintenance of expression of their target gene, HMGA1. Downregulation of HIF1A-AS2 led to delayed growth of mesenchymal GSC tumors, survival benefits, and impaired expression of HMGA1 in vivo. Our data demonstrate that HIF1A-AS2 contributes to GSCs' speciation and adaptation to hypoxia within the tumor microenvironment, acting directly through its interactome and targets and indirectly by modulating responses to hypoxic stress depending on the subtype-specific genetic context.
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Marco
M
Mineo
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
Franz
F
Ricklefs
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Arun K
AK
Rooj
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Shawn M
SM
Lyons
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Pavel
P
Ivanov
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Khairul I
KI
Ansari
Department of Neurosurgery and Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL 35243-2823, USA.
Ichiro
I
Nakano
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: eachiocca@partners.org.
E Antonio
EA
Chiocca
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: jgodlewski@partners.org.
Jakub
J
Godlewski
Harvey Cushing Neuro-Oncology Laboratories, Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: abronisz@partners.org.
Agnieszka
A
Bronisz
D015687:Cell Hypoxia / Q000235:genetics; D045744:Cell Line, Tumor; D019070:Cell Lineage; D018450:Disease Progression; D018740:Genetic Heterogeneity; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000473:pathology*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology*; D062085:RNA, Long Noncoding / Q000235:genetics / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000378:metabolism; D055153:Stem Cell Niche
D062085:RNA, Long Noncoding; D012334:RNA, Neoplasm; C000614114:long noncoding RNA HIF1A-AS2, human