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In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis

Item Type:Article
Title:In vivo RNAi screen for BMI1 targets identifies TGF-β/BMP-ER stress pathways as key regulators of neural- and malignant glioma-stem cell homeostasis
Creators Name:Gargiulo, G. and Cesaroni, M. and Serresi, M. and de Vries, N. and Hulsman, D. and Bruggeman, S.W. and Lancini, C. and van Lohuizen, M.
Abstract:In mouse and human neural progenitor and glioblastoma "stem-like" cells, we identified key targets of the Polycomb-group protein BMI1 by combining ChIP-seq with invivo RNAi screening. We discovered that Bmi1 is important in the cellular response to the transforming growth factor-{beta}/bone morphogenetic protein (TGF-{beta}/BMP) and endoplasmic reticulum (ER) stress pathways, in part converging on the Atf3 transcriptional repressor. We show that Atf3 is a tumor-suppressor gene inactivated in human glioblastoma multiforme together with Cbx7 and a few other candidates. Acting downstream of the ER stress and BMP pathways, ATF3 binds to cell-type-specific accessible chromatin preloaded with AP1 and participates in the inhibition of critical oncogenic networks. Our data support the feasibility of combining ChIP-seq and RNAi screens in solid tumors and highlight multiple p16(INK4a)/p19(ARF)-independent functions for Bmi1 in development and cancer.
Keywords:Activating Transcription Factor 3, Bone Morphogenetic Proteins, Cell Nucleus, Chromatin, Endoplasmic Reticulum Stress, Glioblastoma, Homeostasis, Neoplastic Stem Cells, Neural Stem Cells, Polycomb Repressive Complex 1, Proto-Oncogene Proteins, RNA Interference, Signal Transduction, Transforming Growth Factor {beta}, Animals, Mice
Source:Cancer Cell
ISSN:1535-6108
Publisher:Cell Press / Elsevier (U.S.A.)
Volume:23
Number:5
Page Range:660-676
Date:13 May 2013
Official Publication:https://doi.org/10.1016/j.ccr.2013.03.030
PubMed:View item in PubMed

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