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The growth suppressor PML represses transcription by functionally and physically interacting with histone
1Department of Molecular Pathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
Abstract:
The growth suppressor promyelocytic leukemia protein (PML) is disrupted by the chromosomal translocation t(15;17) in acute promyelocytic leukemia (APL). PML plays a key role in multiple pathways of apoptosis and regulates cell cycle progression. The present study demonstrates that PML represses transcription by functionally and physically interacting with histone deacetylase (HDAC). Transcriptional repression mediated by PML can be inhibited by trichostatin A, a specific inhibitor of HDAC. PML coimmunoprecipitates a significant level of HDAC activity in several cell lines. PML is associated with HDAC in vivo and directly interacts with HDAC in vitro. The fusion protein PML-RARalpha encoded by the t(15;17) breakpoint interacts with HDAC poorly. PML interacts with all three isoforms of HDAC through specific domains, and its expression deacetylates histone H3 in vivo. Together, the results of our study show that PML modulates histone deacetylation and that loss of this function in APL alters chromatin remodeling and gene expression. This event may contribute to the development of leukemia.
Insights
The promyelocytic leukemia protein (PML) normally suppresses growth by interacting with histone deacetylase (HDAC). Loss of this interaction in acute promyelocytic leukemia (APL) may drive cancer development.
Area of Science:
- Molecular Biology
- Cancer Biology
- Epigenetics
Background:
- The promyelocytic leukemia protein (PML) is a tumor suppressor involved in apoptosis and cell cycle regulation.
- Chromosomal translocation t(15;17) disrupts PML in acute promyelocytic leukemia (APL).
Purpose of the Study:
- To investigate the molecular mechanism by which PML regulates gene transcription.
- To determine the role of histone deacetylase (HDAC) in PML-mediated transcriptional repression.
- To explore the functional consequences of PML-HDAC interaction disruption in APL.
Main Methods:
- Coimmunoprecipitation assays to detect PML-HDAC interaction and HDAC activity.
- In vitro binding assays to confirm direct interaction between PML and HDAC.
- In vivo studies using cell lines to assess histone H3 deacetylation.
- Treatment with trichostatin A (HDAC inhibitor) to evaluate transcriptional repression.
Main Results:
- PML physically and functionally interacts with histone deacetylase (HDAC), mediating transcriptional repression.
- This repression is reversible by trichostatin A, a specific HDAC inhibitor.
- PML interacts with HDAC in vivo and in vitro, deacetylating histone H3.
- The oncogenic PML-RARalpha fusion protein shows impaired interaction with HDAC.
- PML interacts with multiple HDAC isoforms through specific domains.
Conclusions:
- PML modulates histone deacetylation, influencing chromatin remodeling and gene expression.
- Disruption of PML-HDAC interaction in APL leads to altered gene expression, potentially contributing to leukemogenesis.
- Understanding PML-HDAC interplay offers potential therapeutic targets for APL.