Abstract
Abstract Glioblastoma (GBM) is the most aggressive primary brain tumor and responds poorly to currently available therapies. Transcriptomic characterization of GBM has identified distinct molecular subtypes of GBM with the latest report identifying four molecular subtypes: proneural, neural, classical, and mesenchymal. Gain-of-function alterations leading to enhanced platelet-derived growth factor (PDGF) signaling are commonly observed in proneural GBM and can drive proneural gliomagenesis. However, little is known about the critical determinants of malignancy mediated by PDGF signaling in proneural glioma. Using a mouse model of proneural glioma and comparative transcriptomics, we determined that PDGF signaling upregulates ubiquitin specific peptidase 1 (Usp1) to promote survival of murine proneural glioma cells. Further experimentation revealed that PDGF-mediated expression of USP1 post-translationally stabilized Inhibitor of DNA-binding 2 (ID2), which we found to be required for glioma cell survival. Deletion of the Id2 gene delayed tumor-induced mortality. Pharmacological inhibition of USP1 decreased ID2 levels, and delayed tumorigenesis in mice. Importantly, decreased USP1 expression is associated with prolonged survival in patients with proneural GBM but not with other subtypes of GBM. Our data describe a signaling cascade downstream of PDGF that is required for the survival of proneural GBM cells and suggest that inhibition of the PDGF-USP1-ID2 axis could serve as a therapeutic strategy for the treatment of proneural GBM with increased PDGF signaling. Citation Format: Gilbert J. Rahme, Zhonghua Zhang, Alison L. Young, Chao Cheng, Eric J. Bivona, Steven N. Fiering, Yasuyuki Hitoshi, Mark A. Israel. PDGF signaling maintains survival of proneural glioma cells by regulating USP1 to stabilize ID2. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1891.
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