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
Autor/innen
- G. Gargiulo
- M. Cesaroni
- M. Serresi
- N. de Vries
- D. Hulsman
- S.W. Bruggeman
- C. Lancini
- M. van Lohuizen
Journal
- Cancer Cell
Quellenangabe
- Canc Cell 23 (5): 660-676
Zusammenfassung
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.