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PMID: 19605626 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

BMI1 sustains human glioblastoma multiforme stem cell renewal.

The Journal of neuroscience : the official journal of the Society for Neuroscience ·Vol. 29 ·No. 28 ·2009-07-15 ·Pages 8884-96

Abdouh M, Facchino S, Chatoo W, Balasingam V, Ferreira J, Bernier G

Abstract

Glioblastoma multiforme (GBM) is one of the most common and aggressive types of brain tumors. In GBM, a subpopulation of CD133-positive cancer initiating cells displays stem cell characteristics. The Polycomb group (PcG) and oncogene BMI1 is part of the Polycomb repressive complex 1 (PRC1) that regulates gene expression by modifying chromatin organization. Here we show that BMI1 is expressed in human GBM tumors and highly enriched in CD133-positive cells. Stable BMI1 knockdown using short hairpin RNA-expressing lentiviruses resulted in inhibition of clonogenic potential in vitro and of brain tumor formation in vivo. Cell biology studies support the notion that BMI1 prevents CD133-positive cell apoptosis and/or differentiation into neurons and astrocytes, depending on the cellular context. Gene expression analyses suggest that BMI1 represses alternate tumor suppressor pathways that attempt to compensate for INK4A/ARF/P53 deletion and PI(3)K/AKT hyperactivity. Inhibition of EZH2, the main component of the PRC2, also impaired GBM tumor growth. Our results reveal that PcG proteins are involved in GBM tumor growth and required to sustain cancer initiating stem cell renewal.

MeSH Terms
AC133 Antigen Analysis of Variance Animals Antigens, CD/metabolism Apoptosis/genetics Brain Neoplasms/pathology Cell Differentiation/physiology Cell Line, Tumor Cell Transdifferentiation Cell Transformation, Neoplastic/metabolism,pathology Cells, Cultured Chromatin Immunoprecipitation/methods DNA-Binding Proteins/genetics,metabolism Disease Models, Animal Enhancer of Zeste Homolog 2 Protein Flow Cytometry Gene Expression Regulation, Neoplastic/genetics Gene Silencing/physiology Glioblastoma/pathology Glycoproteins/metabolism Humans Mice Mice, Inbred NOD/physiology,surgery Mice, SCID/surgery Neoplastic Stem Cells/pathology,physiology Nuclear Proteins/genetics,metabolism Oligonucleotide Array Sequence Analysis/methods Peptides/metabolism Polycomb Repressive Complex 1 Polycomb Repressive Complex 2 Proto-Oncogene Proteins/genetics,metabolism RNA, Small Interfering/genetics,metabolism Repressor Proteins/genetics,metabolism Transcription Factors/genetics,metabolism Tumor Stem Cell Assay/methods
Chemicals
AC133 Antigen Antigens, CD BMI1 protein, human DNA-Binding Proteins Glycoproteins Nuclear Proteins PROM1 protein, human Peptides Prom1 protein, mouse Proto-Oncogene Proteins RNA, Small Interfering Repressor Proteins Transcription Factors EZH2 protein, human Enhancer of Zeste Homolog 2 Protein Polycomb Repressive Complex 2 Polycomb Repressive Complex 1
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Abdouh Mohamed
Developmental Biology Laboratory, Maisonneuve-Rosemont Hospital, Montréal, Québec H1T 2M4, Canada.
Facchino Sabrina
Chatoo Wassim
Balasingam Vijayabalan
Ferreira José
Bernier Gilbert
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Article Info
Journal
The Journal of neuroscience : the official journal of the Society for Neuroscience
Abbr.
J Neurosci
ISSN
1529-2401
DOI
10.1523/JNEUROSCI.0968-09.2009
Published
2009-07-15
Pages
8884-96
Language
English
Region
United States
NLM ID
8102140
PMCID
PMC6665439
Subset
IM
External Links
PubMed source DOI: 10.1523/JNEUROSCI.0968-09.2009 PMC Full Text View journal details
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