CSIG-03. PROLINE GLUTAMIC ACID AND LEUCINE RICH PROTEIN 1 (PELP1) PROMOTES GLIOBLASTOMA PROGRESSION VIA β-CATENIN PATHWAY
Year: 2017
Type: conference-abstract
Abstract: Glioblastomas (GBM) have dismal survival rates (1 year-34.6% and 5 year-4.75%) and affect 13,000 patients per year. Standard treatment consists of surgical resection, external beam radiation therapy, adjuvant chemotherapy with temozolomide and tumor treating fields. Nonetheless, despite a heavy investment in therapy, all patients will eventually succumb to their disease. Delineating the molecular pathways and mechanisms that contribute to the GBM development is clinically significant and provide novel therapeutic options for GBM. In the present study, we examined the significance of coregulator protein Proline Glutamic acid and Leucine rich Protein 1(PELP1) in GBM. Immunohistochemical analysis of glioma tissue microarrays revealed that PELP1 is overexpressed in the glial tumors compared to normal brain, with the highest expression in GBM and TCGA analysis revealed that patients with high PELP1 expression have shorter survival. Knockdown of PELP1 using specific siRNA and shRNA has a dramatic effect on cell proliferation, cell migration and invasion of established and patient-derived GBM cells. Global transcriptomic analysis revealed that PELP1 knockdown significantly downregulated the pathways related to cell survival, migration, and invasion including β-catenin pathway. Further gene set enrichment analysis (GSEA) confirmed that the PELP1-downregulated genes correlated well with signatures of β-catenin pathway. Mechanistic studies showed that PELP1 interacts with β-catenin and PELP1 increases β-catenin reporter gene activation. Accordingly, PELP1 knockdown significantly reduced the expression of β-catenin target genes and chromatin immunoprecipitation assays demonstrated that knockdown of PELP1 attenuated the recruitment of β-catenin to the target genes promoter. Further, knockdown of PELP1 significantly reduced in vivo tumor progression in orthotopic models and improved the overall mice survival. Taken together these results provide the evidence that PELP1 could be a potential therapeutic target for therapeutic intervention in GBM.
Source: Neuro-Oncology
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2767450362