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PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells Gilbert J

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PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells Gilbert J Published OnlineFirst March 7, 2016; DOI: 10.1158/0008-5472.CAN-15-2157 Cancer Molecular and Cellular Pathobiology Research PDGF Engages an E2F-USP1 Signaling Pathway to Support ID2-Mediated Survival of Proneural Glioma Cells Gilbert J. Rahme1,2,3, Zhonghua Zhang2,3,4, Alison L. Young2,3,4, Chao Cheng1,2,3, Eric J. Bivona5, Steven N. Fiering1,2,3, Yasuyuki Hitoshi2,3,4, and Mark A. Israel1,2,3,4 Abstract Glioblastoma is the most aggressive primary brain tumor and activated Usp1. Furthermore, PDGF-mediated expression of responds poorly to currently available therapies. Transcriptomic USP1 led to the stabilization of Inhibitor of DNA-binding 2 characterization of glioblastoma has identified distinct molec- (ID2), which we found to be required for glioma cell survival. ular subtypes of glioblastoma. Gain-of-function alterations Genetic ablation of Id2 delayed tumor-induced mortality, and leading to enhanced platelet-derived growth factor (PDGF) pharmacologic inhibition of USP1, resulting in decreased ID2 signaling are commonly observed in the proneural subtype of levels, also delayed tumorigenesis in mice. Notably, decreased glioblastoma and can drive gliomagenesis. However, little is USP1 expression was associated with prolonged survival in known about the downstream effectors of PDGF signaling in patients with proneural glioblastoma, but not with other sub- glioblastoma. Using a mouse model of proneural glioma and types of glioblastoma. Collectively, our findings describe a comparative transcriptomics, we determined that PDGF signal- signaling cascade downstream of PDGF that sustains proneural ing upregulated ubiquitin-specificpeptidase1(Usp1)topro- glioblastoma cells and suggest that inhibition of the PDGF– mote the survival of murine proneural glioma cells. Mechanis- E2F–USP1–ID2 axis could serve as a therapeutic strategy for tically, we found that PDGF signaling regulated the expression of proneural glioblastoma featuring increased PDGF signaling. the E2F transcription factors, which directly bound to and Cancer Res; 76(10); 2964–76. Ó2016 AACR. Introduction characterized by frequent amplifications in the genomic region encoding the receptor tyrosine kinase (RTK), platelet-derived Glioblastoma is the most lethal and aggressive primary brain growth factor receptor a (PDGFRA; ref. 5). Multiple studies tumor. Despite expansive diagnostic efforts and aggressive com- indicate that increased PDGF signaling is sufficient to drive bination therapy, including surgery, ionizing radiation, and che- gliomagenesis in murine models, emphasizing the importance motherapy, the median survival of patients with glioblastoma of PDGF signaling in glioblastoma (7–12). Transcriptomic char- remains a modest 12–15 months (1, 2). Although described as a acterization of PDGF-induced high-grade glioma in mice revealed single histopathologic entity, transcriptomic profiling of glioblas- a proneural glioblastoma molecular signature, indicating that toma has led to the identification of multiple subtypes (3, 4) with increased PDGF signaling is a driver of proneural gliomagenesis the latest report identifying four subtypes: proneural, neural, (11, 12). Little is known, however, about the precise molecular classical, and mesenchymal glioblastoma (5). Each of these sub- pathways downstream of PDGF signaling causing malignancy in types has an associated profile of genetic alterations (5, 6). proneural glioma. Proneural glioblastoma, which is resistant to current therapy, is Among the cellular processes that are critical for glioblastoma pathology, protein degradation is emerging as an important 1 regulator of tumorigenesis and a target for cancer treatment Department of Genetics, Dartmouth College, Hanover, New Hamp- – shire. 2Norris Cotton Cancer Center, Dartmouth College, Hanover, New (13 15). Ubiquitination and its reverse, deubiquitination, are Hampshire. 3Geisel School of Medicine, Dartmouth College, Hanover, major regulatory pathways that control protein degradation and New Hampshire. 4Department of Pediatrics, Dartmouth College, Han- contribute to cell-cycle regulation, stem cell maintenance, and over, New Hampshire. 5Digital Library Technologies Group, Dartmouth College, Hanover, New Hampshire. cellular survival, as well as other biologic activities of importance for tumorigenesis (16, 17). Although it is known that the cellular Note: Supplementary data for this article are available at Cancer Research localization, posttranslational modification, and altered structure Online (http://cancerres.aacrjournals.org/). of proteins can regulate their degradation (18), the repertoire of Current address for Y. Hitoshi: Department of Neurosurgery, Amakusa Medical molecules that regulates the destruction of specific targets is Center, 854-1 Jikiba Kameba, Amakusa, Kumamoto, Japan. incompletely known. Deubiquitinases (DUB), which include Corresponding Author: Mark A. Israel, Geisel School of Medicine at Dartmouth, over 100 genes classified into five subgroups, catalyze the removal One Medical Center Drive, Lebanon, NH 03756. Phone: 603-653-3611; Fax: 603- of ubiquitin molecules that are covalently bound to a substrate, 653-9003; E-mail: [email protected] thus diminishing its proteasomal degradation (17). Recent work doi: 10.1158/0008-5472.CAN-15-2157 has identified a role for USP1, a member of the ubiquitin-specific Ó2016 American Association for Cancer Research. peptidase (USP) group of DUBs, in the regulation of tumor 2964 Cancer Res; 76(10) May 15, 2016 Downloaded from cancerres.aacrjournals.org on September 24, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst March 7, 2016; DOI: 10.1158/0008-5472.CAN-15-2157 A PDGF-E2F-USP1-ID2 Axis Is Required for Proneural Glioma pathogenesis (19–21) including glioblastoma (22). Inhibition of Transfections USP1 by multiple strategies has been suggested as a potential PDGF-GSCs were transfected using LipoD293 (Signagen) as strategy to enhance the therapeutic efficacy of chemotherapy per product guidelines. and radiation in treating cancer (22–24). USP1, upon forming a molecular complex with UAF1 (WDR48), deubiquitinates sub- Annexin V/PI flow cytometry analysis strates including PCNA, FANCI, FANCD2, and the short-lived Annexin V/PI staining was performed using the Annexin V/PI Inhibitor of DNA Binding (ID) proteins ID1, ID2, and ID3 that Apoptosis Detection Kit II (BD Pharmingen) following the man- each have a half-life of about 10 minutes (19, 20, 25–28). ufacturer's guidelines. The FL1 channel was used to detect Members of the Id gene family, including Id2, have been Annexin V-FITC and the FL3 channel was used to detect PI. proposed as mediators of glioblastoma pathology and are known to be highly expressed in a number of different tumor Western blot analysis types (28–30). Western blot analysis was done as described previously (33). While studying the molecular events underlying the critical The antibodies used and the working dilutions are shown in role of PDGF signaling in proneural glioma, we confirmed the Supplementary Table S1. Antibodies that recognize ID proteins regulation of multiple gene groups by PDGF signaling and were validated in a previous report from our laboratory (33). discovered a previously unknown role for PDGF signaling in the regulation of protein degradation. We found that PDGF RNA extraction and qRT-PCR regulates the transcription of molecules key for protein degra- For microarray analysis, RNA was purified using the TRIzol dation, including E3 ubiquitin ligases, ubiquitin, SUMO (small method. For qRT-PCR, RNA was extracted using the RNeasy kit as ubiquitin-like modifier)-related genes, and DUBs, among per product guidelines (Qiagen). Data were quantified relative to which we found USP1 to be critical for survival of PDGF-driven untreated control in each GSC culture, and normalized either only glioma spheroid cells (referred to as PDGF-GSCs in this study). to 18S Ct values, or 18S Ct values followed by another normal- ÀDDCt In addition, we found that PDGF signaling drives the expres- ization to Id2 Ct values (Supplementary Fig. S6), using the 2 sion of USP1 by upregulating the expression of E2f1, E2f2,and method. Primers are provided in Supplementary Table S2. E2f3 (E2f1-3), transcription factors that interact with the reti- noblastoma protein (pRB), and thereby increases their inter- Chromatin immunoprecipitation analysis action with the Usp1 promoter. Furthermore, we determined Chromatin immunoprecipitation (ChIP) was performed as that ID2 is a critical USP1 substrate that is required for survival ÀDDC described previously (33). Data were analyzed using the 2 t in PDGF-GSCs. Targeting the PDGF-E2F-USP1-ID2 axis by method with normalization to the IgG isotype control ChIP of deletion of the Id2 gene or pharmacologic inhibition of USP1 cells that were treated in a manner identical to the experimental delayed tumorigenesis of PDGF-driven glioma. Importantly, cells. Primer sequences are provided in Supplementary Table S2. data from The Cancer Genome Atlas (TCGA) suggest the presence of a PDGF-USP1 axis in proneural glioblastoma, and that USP1 is a prognostic factor in proneural glioblastoma, but Lentiviral infection not in other subtypes of glioblastoma. These results suggest that Lentiviruses were prepared using 293FT cells with an optimized targeting the PDGF-E2F-USP1-ID2 axis can be a beneficial Signagen protocol. A three-vector second-generation system using treatment strategy for proneural glioma. These findings may pCMV-Delta8.9, pVSVG, and the pLKO.1 transfer vector
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