TY - JOUR
T1 - REST-DRD2 mechanism impacts glioblastoma stem cell-mediated tumorigenesis
AU - Marisetty, Anantha L.
AU - Lu, Li
AU - Veo, Bethany L.
AU - Liu, Bin
AU - Coarfa, Cristian
AU - Kamal, Mohamed Mostafa
AU - Kassem, Dina Hamada
AU - Irshad, Khushboo
AU - Lu, Yungang
AU - Gumin, Joy
AU - Henry, Verlene
AU - Paulucci-Holthauzen, Adriana
AU - Rao, Ganesh
AU - Baladandayuthapani, Veerabhadran
AU - Lang, Frederick F.
AU - Fuller, Gregory N.
AU - Majumder, Sadhan
N1 - Publisher Copyright:
© The Author(s) 2019.
PY - 2019/6/10
Y1 - 2019/6/10
N2 - Background. Glioblastoma (GBM) is a lethal, heterogeneous human brain tumor, with regulatory mechanisms that have yet to be fully characterized. Previous studies have indicated that the transcriptional repressor REST (repressor element-1 silencing transcription factor) regulates the oncogenic potential of GBM stem cells (GSCs) based on level of expression. However, how REST performs its regulatory role is not well understood. Methods. We examined 2 independent high REST (HR) GSC lines using genome-wide assays, biochemical validations, gene knockdown analysis, and mouse tumor models. We analyzed in-house patient tumors and patient data present in The Cancer Genome Atlas (TCGA). Results. Genome-wide transcriptome and DNA-binding analyses suggested the dopamine receptor D2 (DRD2) gene, a dominant regulator of neurotransmitter signaling, as a direct target of REST. Biochemical analyses and mouse intracranial tumor models using knockdown of REST and double knockdown of REST and DRD2 validated this target and suggested that DRD2 is a downstream target of REST regulating tumorigenesis, at least in part, through controlling invasion and apoptosis. Further, TCGA GBM data support the presence of the REST-DRD2 axis and reveal that high REST/low DRD2 (HRLD) and low REST/high DRD2 (LRHD) tumors are specific subtypes, are molecularly different from the known GBM subtypes, and represent functional groups with distinctive patterns of enrichment of gene sets and biological pathways. The inverse HRLD/LRHD expression pattern is also seen in in-house GBM tumors. Conclusions. These findings suggest that REST regulates neurotransmitter signaling pathways through DRD2 in HR-GSCs to impact tumorigenesis. They further suggest that the REST-DRD2 mechanism forms distinct subtypes of GBM.
AB - Background. Glioblastoma (GBM) is a lethal, heterogeneous human brain tumor, with regulatory mechanisms that have yet to be fully characterized. Previous studies have indicated that the transcriptional repressor REST (repressor element-1 silencing transcription factor) regulates the oncogenic potential of GBM stem cells (GSCs) based on level of expression. However, how REST performs its regulatory role is not well understood. Methods. We examined 2 independent high REST (HR) GSC lines using genome-wide assays, biochemical validations, gene knockdown analysis, and mouse tumor models. We analyzed in-house patient tumors and patient data present in The Cancer Genome Atlas (TCGA). Results. Genome-wide transcriptome and DNA-binding analyses suggested the dopamine receptor D2 (DRD2) gene, a dominant regulator of neurotransmitter signaling, as a direct target of REST. Biochemical analyses and mouse intracranial tumor models using knockdown of REST and double knockdown of REST and DRD2 validated this target and suggested that DRD2 is a downstream target of REST regulating tumorigenesis, at least in part, through controlling invasion and apoptosis. Further, TCGA GBM data support the presence of the REST-DRD2 axis and reveal that high REST/low DRD2 (HRLD) and low REST/high DRD2 (LRHD) tumors are specific subtypes, are molecularly different from the known GBM subtypes, and represent functional groups with distinctive patterns of enrichment of gene sets and biological pathways. The inverse HRLD/LRHD expression pattern is also seen in in-house GBM tumors. Conclusions. These findings suggest that REST regulates neurotransmitter signaling pathways through DRD2 in HR-GSCs to impact tumorigenesis. They further suggest that the REST-DRD2 mechanism forms distinct subtypes of GBM.
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U2 - 10.1093/neuonc/noz030
DO - 10.1093/neuonc/noz030
M3 - Article
C2 - 30953587
AN - SCOPUS:85067633905
SN - 1522-8517
VL - 21
SP - 775
EP - 785
JO - Neuro-oncology
JF - Neuro-oncology
IS - 6
ER -