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Published on: August 12, 2015
BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner
Wenwen Zhang1, Jiayan Luo1, Fengxia Chen1
1Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.
Abstract:
BRCA1 plays a key role in the regulation of p53-dependent target gene transcription activation. Meanwhile, the p53 inducible gene 3 (PIG3) is a downstream target of p53 and is involved in p53-initiated apoptosis. However, little is known about whether BRCA1 can regulate PIG3-mediated apoptosis. Using a tissue microarray containing 149 breast cancer patient samples, we found that BRCA1 and PIG3 expression status were significantly positively correlated (r = 0.678, P < 0.001) and identified a significant positive correlation between high expression of BRCA1 and/or PIG3 and overall survival (OS). Moreover, we reveal that overexpression of BRCA1 significantly increased expression of PIG3 in cells with intact p53, whereas no increase in PIG3 was observed in p53-null MDA-MB-157 cells and p53-depleted HCT116p53-/- cells. Meanwhile, ectopic expression of BRCA1 could not lead to an increase expression level of prohibitin (PHB), which we have previously identified to induce PIG3-mediated apoptosis. Finally, ChIP analysis revealed that PHB can bind to the PIG3 promoter and activate PIG3 transcription independent of p53, although p53 presence did enhance this process. Taken together, our findings suggest that BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner, and that PIG3 expression is associated with a better OS in breast cancer patients.
Insights
BRCA1 regulates apoptosis by increasing PIG3 expression in a p53-dependent manner. High BRCA1 and PIG3 expression in breast cancer patients correlates with better overall survival.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- BRCA1 is crucial for p53-dependent gene transcription.
- PIG3, a p53 target gene, mediates apoptosis.
- The role of BRCA1 in PIG3-mediated apoptosis is unclear.
Purpose of the Study:
- To investigate whether BRCA1 regulates PIG3-mediated apoptosis.
- To explore the correlation between BRCA1, PIG3 expression, and overall survival in breast cancer.
- To elucidate the mechanism of BRCA1 in PIG3 regulation.
Main Methods:
- Analysis of a tissue microarray from 149 breast cancer patients.
- Cell-based assays to assess PIG3 expression following BRCA1 overexpression in cells with varying p53 status.
- Chromatin immunoprecipitation (ChIP) assays to determine PHB binding to the PIG3 promoter.
Main Results:
- Significant positive correlation found between BRCA1 and PIG3 expression (r = 0.678, P < 0.001).
- High BRCA1/PIG3 expression correlated with improved overall survival.
- BRCA1 overexpression increased PIG3 levels in p53-intact cells but not in p53-null or depleted cells.
- Prohibitin (PHB) binds to the PIG3 promoter, activating transcription independently of p53, though p53 enhances the process.
Conclusions:
- BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner.
- PIG3 expression is a favorable prognostic marker associated with better overall survival in breast cancer patients.
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