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Yong Jae Shin1,2,3*, Jason K. Sa1,2*, Yeri Lee1,2, Donggeon Kim1,2, Nakho Chang4, Hee Jin Cho1,2, Miseol Son1,9, Michael Y.T. Oh5, Kayoung Shin1,6, Jin-Ku Lee1,2, Jiwon Park1, Yoon Kyung Jo1,2, Misuk Kim1,2, Patrick J. Paddison7, Vinay Tergaonkar9,10, Jeongwu Lee8 and Do-Hyun Nam1,2,3,6
1Institute for Refractory Cancer Research, Samsung Medical Center, Seoul, Korea; 2Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea; 3Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea; 4Yuhan Research Institute, Yongin, Korea; 5Institute for Cancer Genetics ,Columbia University Medical Center, New York, NY; 6Department of Health Sciences and Technology, Samsung Advanced Institute for Health Science and Technology, Sungkyunkwan University, Seoul, Korea; 7Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA; 8Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH; 9Division of Cancer Cell Signaling, Institute of Molecular and Cell Biology, Singapore; 10Departmentof Pathology, National University of Singapore, Singapore.
*Y.J. Shin and J.K. Sa contributed equally to this paper
Correspondence to Do-Hyun Nam, Jeongwu Lee
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.
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