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.

Gargiulo G, Cesaroni M, Serresi M, de Vries N, Hulsman D, Bruggeman SW, Lancini C, van Lohuizen M
Cancer Cell. 2013 23 (5): 660-76

PMID: 23680149 · DOI:10.1016/j.ccr.2013.03.030

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 in vivo RNAi screening. We discovered that Bmi1 is important in the cellular response to the transforming growth factor-β/bone morphogenetic protein (TGF-β/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.

Copyright © 2013 Elsevier Inc. All rights reserved.

MeSH Terms (17)

Activating Transcription Factor 3 Animals Bone Morphogenetic Proteins Cell Nucleus Chromatin Endoplasmic Reticulum Stress Glioblastoma Homeostasis Humans Mice Neoplastic Stem Cells Neural Stem Cells Polycomb Repressive Complex 1 Proto-Oncogene Proteins RNA Interference Signal Transduction Transforming Growth Factor beta

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