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BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner.

Zhang W, Luo J, Chen F, Yang F, Song W, Zhu A, Guan X - Oncotarget (2015)

Bottom Line: 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- 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.

View Article: PubMed Central - PubMed

Affiliation: Department 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- 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.

No MeSH data available.


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Schematic model depicting the critical role of BRCA1 in the regulation of PIG3-mediated apoptosis
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Figure 5: Schematic model depicting the critical role of BRCA1 in the regulation of PIG3-mediated apoptosis

Mentions: Collectively, our results to date permit construction of a schematic model demonstrating the critical role of BRCA1 in the regulation of PIG3-mediated apoptosis (Figure 5). Most importantly, key features of this pathway are manifested in clinical breast cancer patients. Importantly, our data reveal that BRCA1 positively regulates PIG3 expression in a p53-dependent manner, and the clinical data demonstrate a statistically significant positive correlation between PIG3 and BRCA1 expression, with high PIG3 and/or BRCA1 expression were associated with better OS in human breast cancer patients. Together, our results provide a mechanism for how BRCA1 regulates PIG3 expression and illustrate the relevance of this mechanism to clinical outcomes in breast cancer patients. However, additional larger studies and more detailed investigations of the regulatory mechanisms underlying the influence of BRCA1 on the expression of PIG3 are needed to validate our findings.


BRCA1 regulates PIG3-mediated apoptosis in a p53-dependent manner.

Zhang W, Luo J, Chen F, Yang F, Song W, Zhu A, Guan X - Oncotarget (2015)

Schematic model depicting the critical role of BRCA1 in the regulation of PIG3-mediated apoptosis
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4480703&req=5

Figure 5: Schematic model depicting the critical role of BRCA1 in the regulation of PIG3-mediated apoptosis
Mentions: Collectively, our results to date permit construction of a schematic model demonstrating the critical role of BRCA1 in the regulation of PIG3-mediated apoptosis (Figure 5). Most importantly, key features of this pathway are manifested in clinical breast cancer patients. Importantly, our data reveal that BRCA1 positively regulates PIG3 expression in a p53-dependent manner, and the clinical data demonstrate a statistically significant positive correlation between PIG3 and BRCA1 expression, with high PIG3 and/or BRCA1 expression were associated with better OS in human breast cancer patients. Together, our results provide a mechanism for how BRCA1 regulates PIG3 expression and illustrate the relevance of this mechanism to clinical outcomes in breast cancer patients. However, additional larger studies and more detailed investigations of the regulatory mechanisms underlying the influence of BRCA1 on the expression of PIG3 are needed to validate our findings.

Bottom Line: 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- 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.

View Article: PubMed Central - PubMed

Affiliation: Department 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- 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.

No MeSH data available.


Related in: MedlinePlus