title: PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells.
abstract: Glioblastoma is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of glioblastoma has identified distinct molecular subtypes of glioblastoma. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in the proneural subtype of glioblastoma and can drive gliomagenesis. However, little is known about the downstream effectors of PDGF signaling in glioblastoma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulated ubiquitin-specific peptidase 1 (Usp1) to promote the survival of murine proneural glioma cells. Mechanistically, we found that PDGF signaling regulated the expression of the E2F transcription factors, which directly bound to and activated Usp1 Furthermore, PDGF-mediated expression of USP1 led to the stabilization of Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Genetic ablation of Id2 delayed tumor-induced mortality, and pharmacologic inhibition of USP1, resulting in decreased ID2 levels, also delayed tumorigenesis in mice. Notably, decreased USP1 expression was associated with prolonged survival in patients with proneural glioblastoma, but not with other subtypes of glioblastoma. Collectively, our findings describe a signaling cascade downstream of PDGF that sustains proneural glioblastoma cells and suggest that inhibition of the PDGF-E2F-USP1-ID2 axis could serve as a therapeutic strategy for proneural glioblastoma featuring increased PDGF signaling. Cancer Res; 76(10); 2964-76. ©2016 AACR.
authors.affiliation: Department of Genetics, Dartmouth College, Hanover, New Hampshire. Norris Cotton Cancer Center, Dartmouth College, Hanover, New Hampshire. Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
authors.forename: Gilbert J
authors.initials: GJ
authors.lastname: Rahme
authors.affiliation: Norris Cotton Cancer Center, Dartmouth College, Hanover, New Hampshire. Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. Department of Pediatrics, Dartmouth College, Hanover, New Hampshire.
authors.forename: Zhonghua
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Norris Cotton Cancer Center, Dartmouth College, Hanover, New Hampshire. Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. Department of Pediatrics, Dartmouth College, Hanover, New Hampshire.
authors.forename: Alison L
authors.initials: AL
authors.lastname: Young
authors.affiliation: Department of Genetics, Dartmouth College, Hanover, New Hampshire. Norris Cotton Cancer Center, Dartmouth College, Hanover, New Hampshire. Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
authors.forename: Chao
authors.initials: C
authors.lastname: Cheng
authors.affiliation: Digital Library Technologies Group, Dartmouth College, Hanover, New Hampshire.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Bivona
authors.affiliation: Department of Genetics, Dartmouth College, Hanover, New Hampshire. Norris Cotton Cancer Center, Dartmouth College, Hanover, New Hampshire. Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire.
authors.forename: Steven N
authors.initials: SN
authors.lastname: Fiering
authors.affiliation: Norris Cotton Cancer Center, Dartmouth College, Hanover, New Hampshire. Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. Department of Pediatrics, Dartmouth College, Hanover, New Hampshire.
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Hitoshi
authors.affiliation: Department of Genetics, Dartmouth College, Hanover, New Hampshire. Norris Cotton Cancer Center, Dartmouth College, Hanover, New Hampshire. Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire. Department of Pediatrics, Dartmouth College, Hanover, New Hampshire. Mark.A.Israel@Dartmouth.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Israel
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D050687:E2F1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D005910:Glioma / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D051797:Inhibitor of Differentiation Protein 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D064570:Ubiquitin-Specific Proteases / Q000235:genetics / Q000378:metabolism*
chemical_list: D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C497450:ID2 protein, human; D051797:Inhibitor of Differentiation Protein 2; D020574:Proto-Oncogene Proteins c-sis; D012333:RNA, Messenger; C579228:USP1 protein, human; D064570:Ubiquitin-Specific Proteases