Ezh2 reduces the ability of HDAC1-dependent pRb2/p130 transcriptional repression of cyclin A.
The polycomb group (PcG) proteins are known to be involved in maintaining the silenced state of several developmentally regulated genes. Enhancer of zeste homolog 2 (Ezh2), a member of this large protein family, has also been shown to be deregulated in different tumor types and its role, both as a ... potential primary effector and as a mediator of tumorigenesis, has become a subject of increased interest. We observed that Ezh2 binds to pRb2/p130, a member of the retinoblastoma family; as such, we were led to consider the possible ability of Ezh2 to modulate cell cycle progression. Both Ezh2 and pRb2/p130 repress gene expression by recruiting histone deacetylase (HDAC1), which decreases DNA accessibility for activating transcription factors. Additionally, we observed that Ezh2 interacts with the C-terminal region of pRb2/p130, essential for interaction with HDAC1. We show that Ezh2 is able to reverse pRb2/p130-HDAC1-mediated repression of the cyclin A promoter. This indicates a functional role of this complex in regulating cyclin A expression, known to be crucial in mediating cell cycle advancement. We also detected a significant decrease in the retention of HDAC1 activity associated with pRb2/p130 when Ezh2 was overexpressed. Finally, electromobility shift assays (EMSA) demonstrated that overexpression of Ezh2 caused the abrogation of the pRb2/p130-HDAC1 complex on the cyclin A promoter. These data, taken together, suggest that Ezh2 competes with HDAC1 in binding to pRb2/p130, disrupting their occupancy on the cyclin A promoter. In this study, we propose a new mechanism for the functional inactivation of pRb2/p130 that ultimately contributes to cell cycle progression and malignant transformation.
Mesh Terms:
3T3 Cells, Animals, Breast Neoplasms, Cell Line, Cell Line, Tumor, Cyclin A, DNA-Binding Proteins, Female, Histone Deacetylase 1, Histone Deacetylases, Histone-Lysine N-Methyltransferase, Humans, Male, Mice, Plasmids, Prostate, Prostatic Neoplasms, Proteins, Retinoblastoma-Like Protein p130, Transcription Factors, Transcription, Genetic
3T3 Cells, Animals, Breast Neoplasms, Cell Line, Cell Line, Tumor, Cyclin A, DNA-Binding Proteins, Female, Histone Deacetylase 1, Histone Deacetylases, Histone-Lysine N-Methyltransferase, Humans, Male, Mice, Plasmids, Prostate, Prostatic Neoplasms, Proteins, Retinoblastoma-Like Protein p130, Transcription Factors, Transcription, Genetic
Oncogene
Date: Jun. 17, 2004
PubMed ID: 15077161
View in: Pubmed Google Scholar
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