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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

Authors

  • G. Gargiulo
  • M. Cesaroni
  • M. Serresi
  • N. de Vries
  • D. Hulsman
  • S.W. Bruggeman
  • C. Lancini
  • M. van Lohuizen

Journal

  • Cancer Cell

Citation

  • Canc Cell 23 (5): 660-676

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.


DOI

doi:10.1016/j.ccr.2013.03.030