title: Id-1 is a key transcriptional regulator of glioblastoma aggressiveness and a novel therapeutic target.
abstract: Glioblastoma is the most common form of primary adult brain tumors. A majority of glioblastomas grow invasively into distant brain tissue, leading to tumor recurrence, which is ultimately incurable. It is, therefore, essential to discover master regulators that control glioblastoma invasiveness and target them therapeutically. We show here that the transcriptional regulator Id-1 plays a critical role in modulating the invasiveness of glioblastoma cell lines and primary glioblastoma cells. Id-1 expression levels positively correlate with glioma cell invasiveness in culture and with histopathologic grades in patient biopsies. Id-1 knockdown dramatically reduces glioblastoma cell invasion that is accompanied by profound morphologic changes and robust reduction in expression levels of "mesenchymal" markers, as well as inhibition of self-renewal potential and downregulation of glioma stem cell markers. Importantly, genetic knockdown of Id-1 leads to a significant increase in survival in an orthotopic model of human glioblastoma. Furthermore, we show that a nontoxic compound, cannabidiol, significantly downregulates Id-1 gene expression and associated glioma cell invasiveness and self-renewal. In addition, cannabidiol significantly inhibits the invasion of glioblastoma cells through an organotypic brain slice and glioma progression in vivo. Our results suggest that Id-1 regulates multiple tumor-promoting pathways in glioblastoma and that drugs targeting Id-1 represent a novel and promising strategy for improving the therapy and outcome of patients with glioblastoma.
authors.affiliation: Authors' Affiliation: California Pacific Medical Center, Research Institute, San Francisco, California.
authors.forename: Liliana
authors.initials: L
authors.lastname: Soroceanu
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Murase
authors.forename: Chandani
authors.initials: C
authors.lastname: Limbad
authors.forename: Eric
authors.initials: E
authors.lastname: Singer
authors.forename: Juanita
authors.initials: J
authors.lastname: Allison
authors.forename: Isabel
authors.initials: I
authors.lastname: Adrados
authors.forename: Rumi
authors.initials: R
authors.lastname: Kawamura
authors.forename: Arash
authors.initials: A
authors.lastname: Pakdel
authors.forename: Yayoi
authors.initials: Y
authors.lastname: Fukuyo
authors.forename: Daniel
authors.initials: D
authors.lastname: Nguyen
authors.forename: Sabeena
authors.initials: S
authors.lastname: Khan
authors.forename: Robert
authors.initials: R
authors.lastname: Arauz
authors.forename: Garret L
authors.initials: GL
authors.lastname: Yount
authors.forename: Dan H
authors.initials: DH
authors.lastname: Moore
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Desprez
authors.forename: Sean D
authors.initials: SD
authors.lastname: McAllister
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology; D002185:Cannabidiol / Q000494:pharmacology; D045744:Cell Line, Tumor; D005260:Female; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051798:Inhibitor of Differentiation Protein 1 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000235:genetics*; D009491:Neurospora; D034622:RNA Interference; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: C497453:ID1 protein, human; D051798:Inhibitor of Differentiation Protein 1; D002185:Cannabidiol