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Genome analysis identifies the p15ink4b tumor suppressor as a direct target of the ZNF217/CoREST complex
Gobi Thillainadesan1, Majdina Isovic, Esther Loney
1Department of Oncology, London Regional Cancer Program and The Lawson Health Research Institute, London, Ontario, Canada.
Abstract:
The ZNF217 oncoprotein is a constituent of a core transcriptional complex that includes CoREST, histone deacetylase 1/2, lysine demethylase 1, and the C-terminal binding protein 1/2. We have combined genome-wide expression profiling and chromatin immunoprecipitation with directed selection and ligation (ChIP-DSL) to identify a subset of genes directly regulated by ZNF217. Our results establish p15(ink4b) as a direct target of the ZNF217 complex. Downregulation of ZNF217 in MCF-7 breast cancer cells resulted in a dramatic increase in p15(ink4b) expression and coincided with increases in dimethylation of H3-K4 and, surprisingly, a decrease in K9/K14-H3 acetylation. Stimulation of HaCaT cells with transforming growth factor beta (TGF-beta) resulted in a release of ZNF217 and a concomitant binding of SMAD2 to the proximal promoter, which preceded increases in ink4b protein expression. Furthermore, the changes in chromatin marks at the p15(ink4b) promoter following TGF-beta stimulation were similar to those observed following ZNF217 downregulation. Collectively, these results establish the ZNF217 complex as a novel negative regulator of the p15(ink4b) gene and may constitute an important link between amplification of ZNF217 and the loss of TGF-beta responsiveness in breast cancer.
Insights
The ZNF217 complex directly regulates the p15(ink4b) gene, acting as a negative regulator. This finding links ZNF217 amplification to reduced TGF-beta responsiveness in breast cancer.
Area of Science:
- Molecular biology
- Cancer research
- Epigenetics
Background:
- The ZNF217 oncoprotein is part of a transcriptional complex involved in gene regulation.
- Understanding ZNF217's targets is crucial for deciphering its role in cancer.
Purpose of the Study:
- To identify genes directly regulated by the ZNF217 complex.
- To elucidate the mechanism by which ZNF217 influences p15(ink4b) expression and TGF-beta signaling.
Main Methods:
- Genome-wide expression profiling.
- Chromatin immunoprecipitation with directed selection and ligation (ChIP-DSL).
- Analysis of chromatin modifications (histone methylation and acetylation) and protein binding (SMAD2).
Main Results:
- p15(ink4b) was identified as a direct target gene of the ZNF217 complex.
- ZNF217 downregulation in breast cancer cells increased p15(ink4b) expression and altered specific histone marks.
- Transforming growth factor beta (TGF-beta) stimulation led to ZNF217 release and SMAD2 binding at the p15(ink4b) promoter, preceding increased p15(ink4b) levels.
Conclusions:
- The ZNF217 complex is a novel negative regulator of the p15(ink4b) gene.
- ZNF217 may mediate the loss of TGF-beta responsiveness observed in breast cancers with ZNF217 amplification.
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