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PIP4K2A as a negative regulator of PI3K in PTEN - deficient glioblastoma.
- Source :
-
The Journal of experimental medicine [J Exp Med] 2019 May 06; Vol. 216 (5), pp. 1120-1134. Date of Electronic Publication: 2019 Mar 21. - Publication Year :
- 2019
-
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.<br /> (© 2019 Shin et al.)
- Subjects :
- Animals
Brain Neoplasms pathology
Carcinogenesis metabolism
Cell Proliferation genetics
Cells, Cultured
Class Ia Phosphatidylinositol 3-Kinase genetics
Female
Glioblastoma pathology
Heterografts
Humans
Mice
Mice, Inbred BALB C
Mice, Nude
Phosphotransferases (Alcohol Group Acceptor) genetics
RNA Interference
Transduction, Genetic
Tumor Burden genetics
Brain Neoplasms metabolism
Class Ia Phosphatidylinositol 3-Kinase metabolism
Glioblastoma metabolism
PTEN Phosphohydrolase metabolism
Phosphotransferases (Alcohol Group Acceptor) metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1540-9538
- Volume :
- 216
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- The Journal of experimental medicine
- Publication Type :
- Academic Journal
- Accession number :
- 30898893
- Full Text :
- https://doi.org/10.1084/jem.20172170