Abstract
Glioblastoma (GBM) is the most malignant brain tumor with profound genomic alterations. Tumor suppressor genes regulate multiple signaling networks that restrict cellular proliferation and present barriers to malignant transformation. While bona fide tumor suppressors such as PTEN and TP53 often undergo inactivation due to mutations, there are several genes for which genomic deletion is the primary route for tumor progression. To functionally identify putative tumor suppressors in GBM, we employed in vivo RNAi screening using patient-derived xenograft models. Here, we identified PIP4K2A, whose functional role and clinical relevance remain unexplored in GBM. We discovered that PIP4K2A negatively regulates phosphoinositide 3-kinase (PI3K) signaling via p85/p110 component degradation in PTEN-deficient GBMs and specifically targets p85 for proteasome-mediated degradation. Overexpression of PIP4K2A suppressed cellular and clonogenic growth in vitro and impeded tumor growth in vivo. Our results unravel a novel tumor-suppressive role of PIP4K2A for the first time and support the feasibility of combining oncogenomics with in vivo RNAi screen.
Highlights
Glioblastoma (GBM; World Health Organization grade IV) is the most lethal primary brain tumor with standard-of-care therapies providing only partial palliation (Louis et al, 2007)
We have discovered that PIP4K2A competes with Phosphatase and tensin homologue (PTEN) for physical interaction with p85 and induces proteasomemediated degradation, demonstrating an essential tumor suppressive role in GBM
As genomic deletion is one of the key elements behind malignant transformation, we sought to determine putative tumor suppressor genes using genomic and transcriptome data of GBM patient specimens (n = 228) that are available from the Rembrandt database
Summary
Glioblastoma (GBM; World Health Organization grade IV) is the most lethal primary brain tumor with standard-of-care therapies providing only partial palliation (Louis et al, 2007). In the majority of cancer patients, including those with GBM, malignancies develop due to abnormalities in the structure and orientation of oncogenes and/or tumor suppressor genes. Inactivation of tumor suppressors results from genetic alterations, including genomic mutations, allelic deletions, structure variations, as well as epigenetic silencing due to DNA methylation (Baylin, 2005). Phosphatidylinositol signaling has been shown to impact a variety of fundamental cellular processes, including intracellular membrane trafficking, cytoskeletal rearrangement, and cell proliferation, survival, and growth. Dysregulation of these pathways could lead to malignant transformation into cancer or other diseases
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