The Bmi-1 polycomb protein antagonizes the (-)-epigallocatechin-3-gallate-dependent suppression of skin cancer cell survival
Open Access
- 16 December 2009
- journal article
- Published by Oxford University Press (OUP) in Carcinogenesis: Integrative Cancer Research
- Vol. 31 (3), 496-503
- https://doi.org/10.1093/carcin/bgp314
Abstract
The polycomb group (PcG) proteins are epigenetic regulators of gene expression that enhance cell survival. This regulation is achieved via action of two multiprotein PcG complexes--PRC2 (EED) and PRC1 [B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi-1)]. These complexes modulate gene expression by increasing histone methylation and reducing acetylation--leading to a closed chromatin conformation. Activity of these proteins is associated with increased cell proliferation and survival. We show increased expression of key PcG proteins in immortalized keratinocytes and skin cancer cell lines. We examine the role of two key PcG proteins, Bmi-1 and enhancer of zeste homolog 2 (Ezh2), and the impact of the active agent in green tea, (-)-epigallocatechin-3-gallate (EGCG), on the function of these regulators. EGCG treatment of SCC-13 cells reduces Bmi-1 and Ezh2 level and this is associated with reduced cell survival. The reduction in survival is associated with a global reduction in histone H3 lysine 27 trimethylation, a hallmark of PRC2 complex action. This change in PcG protein expression is associated with reduced expression of key proteins that enhance progression through the cell cycle [cyclin-dependent kinase (cdk)1, cdk2, cdk4, cyclin D1, cyclin E, cyclin A and cyclin B1] and increased expression of proteins that inhibit cell cycle progression (p21 and p27). Apoptosis is also enhanced, as evidenced by increased caspase 9, 8 and 3 cleavage and increased poly(adenosine diphosphate ribose) polymerase cleavage. EGCG treatment also increases Bax and suppresses Bcl-xL expression. Vector-mediated enhanced Bmi-1 expression reverses these EGCG-dependent changes. These findings suggest that green tea polyphenols reduce skin tumor cell survival by influencing PcG-mediated epigenetic regulatory mechanisms.Keywords
This publication has 61 references indexed in Scilit:
- Bmi-1 over-expression in neural stem/progenitor cells increases proliferation and neurogenesis in culture but has little effect on these functions in vivoDevelopmental Biology, 2009
- Bmi-1 cooperates with Foxg1 to maintain neural stem cell self-renewal in the forebrainGenes & Development, 2009
- Ezh2 Requires PHF1 To Efficiently Catalyze H3 Lysine 27 Trimethylation In VivoMolecular and Cellular Biology, 2008
- Expression of Bmi-1 in Epidermis Enhances Cell Survival by Altering Cell Cycle Regulatory Protein Expression and Inhibiting ApoptosisJournal of Investigative Dermatology, 2008
- Bmi-1 Cooperates with H-Ras to Transform Human Mammary Epithelial Cells via Dysregulation of Multiple Growth-Regulatory PathwaysCancer Research, 2007
- Pharmacologic disruption of Polycomb-repressive complex 2-mediated gene repression selectively induces apoptosis in cancer cellsGenes & Development, 2007
- Elevated Bmi-1 expression is associated with dysplastic cell transformation during oral carcinogenesis and is required for cancer cell replication and survivalBritish Journal of Cancer, 2006
- Role of Bmi-1 and Ring1A in H2A Ubiquitylation and Hox Gene SilencingMolecular Cell, 2005
- SUZ12 Is Required for Both the Histone Methyltransferase Activity and the Silencing Function of the EED-EZH2 ComplexMolecular Cell, 2004
- Histone methyltransferase activity associated with a human multiprotein complex containing the Enhancer of Zeste proteinGenes & Development, 2002