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Published on: January 1, 2018
Role of the proto-oncogene Pokemon in cellular transformation and ARF repression
Takahiro Maeda1, Robin M Hobbs, Taha Merghoub
1Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, Sloan-Kettering Institute, 1275 York Avenue, New York, New York 10021, USA.
Abstract:
Aberrant transcriptional repression through chromatin remodelling and histone deacetylation has been postulated to represent a driving force underlying tumorigenesis because histone deacetylase inhibitors have been found to be effective in cancer treatment. However, the molecular mechanisms by which transcriptional derepression would be linked to tumour suppression are poorly understood. Here we identify the transcriptional repressor Pokemon (encoded by the Zbtb7 gene) as a critical factor in oncogenesis. Mouse embryonic fibroblasts lacking Zbtb7 are completely refractory to oncogene-mediated cellular transformation. Conversely, Pokemon overexpression leads to overt oncogenic transformation both in vitro and in vivo in transgenic mice. Pokemon can specifically repress the transcription of the tumour suppressor gene ARF through direct binding. We find that Pokemon is aberrantly overexpressed in human cancers and that its expression levels predict biological behaviour and clinical outcome. Pokemon's critical role in cellular transformation makes it an attractive target for therapeutic intervention.
Insights
The transcriptional repressor Pokemon (Zbtb7) drives oncogenesis by repressing the tumor suppressor ARF. Inhibiting Pokemon may offer a novel cancer therapy by restoring tumor suppressor function.
Area of Science:
- Molecular Biology
- Oncology
- Epigenetics
Background:
- Aberrant transcriptional repression via chromatin remodeling and histone deacetylation is implicated in tumorigenesis.
- Histone deacetylase inhibitors show efficacy in cancer treatment, but mechanisms linking transcriptional derepression to tumor suppression are unclear.
Purpose of the Study:
- To identify key factors in oncogenesis and understand the molecular mechanisms of transcriptional repression in cancer.
- To investigate the role of the transcriptional repressor Pokemon (Zbtb7) in cellular transformation and tumorigenesis.
Main Methods:
- Investigated the function of Zbtb7 in mouse embryonic fibroblasts.
- Utilized in vitro and in vivo transgenic mouse models to study Pokemon's oncogenic potential.
- Analyzed Pokemon's direct binding and repression of the ARF tumor suppressor gene.
- Examined Pokemon expression levels in human cancers.
Main Results:
- Zbtb7-deficient mouse embryonic fibroblasts were resistant to oncogene-mediated transformation.
- Pokemon overexpression induced cellular transformation in vitro and in vivo.
- Pokemon directly binds and represses the transcription of the tumor suppressor gene ARF.
- Aberrant Pokemon overexpression in human cancers correlates with poor prognosis.
Conclusions:
- Pokemon (Zbtb7) is a critical oncogenic factor essential for cellular transformation.
- Pokemon's repression of ARF contributes to its oncogenic activity.
- Pokemon overexpression in human cancers suggests its potential as a therapeutic target.
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