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Transcriptional regulation of the p73 gene by Nrf-2 and promoter CpG methylation in human breast cancer.

Lai J, Nie W, Zhang W, Wang Y, Xie R, Wang Y, Gu J, Xu J, Song W, Yang F, Huang G, Cao P, Guan X - Oncotarget (2014)

Bottom Line: However, we found Nrf-2 induced ΔNp73 expression was abolished with 5-aza-dC treatment, thus lead to a down-regulated ΔNp73 and an up-regulated TAp73 expression in breast cancer cells lines.A significant inverse correlation was found between TAp73 and ΔNp73 expression in the above tissue-array (P = 0.047) and validated in another set consisting of 128 breast cancer tumor tissue (P = 0.034).Taken together, our findings suggest that Nrf-2 and promoter methylation cooperatively govern the transcriptional regulation of p73, and unbalanced expression of TAp73 and ΔNp73 expression plays a critical role in breast cancer development.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Southern Medical University, Guangzhou, China; These authors contributed equally to this work.

ABSTRACT
To understand the transcriptional regulation of p73 by promoter methylation and Nrf-2 in breast carcinogenesis, ChIP assay indicated that Nrf-2 can bind to both promoters and can activate the transcription of TAp73 and ΔNp73 in MCF-7 cell line, knockdown of Nrf-2 gene resulted in an abrogation of TAp73 and ΔNp73 expression in the cells transfected with sh-Nrf-2 as well as Nrf-2 knock out mouse model. However, we found Nrf-2 induced ΔNp73 expression was abolished with 5-aza-dC treatment, thus lead to a down-regulated ΔNp73 and an up-regulated TAp73 expression in breast cancer cells lines. Consistent with this model, we detected decreased TAp73 and increased ΔNp73 expression in breast cancer tissue, along with increased TAp73 but decreased ΔNp73 expression in corresponding surrounding noncancerous tissues (NCTs) in a breast cancer tissue assay. A significant inverse correlation was found between TAp73 and ΔNp73 expression in the above tissue-array (P = 0.047) and validated in another set consisting of 128 breast cancer tumor tissue (P = 0.034). Taken together, our findings suggest that Nrf-2 and promoter methylation cooperatively govern the transcriptional regulation of p73, and unbalanced expression of TAp73 and ΔNp73 expression plays a critical role in breast cancer development.

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A schematic model of dynamic regulation of TAp73 and ΔNp73 expressionA schematic model of dynamic regulation of TAp73 and ΔNp73 expression by Nrf-2-mediated transcriptional activation and CpG island methylation induced transcriptional suppression. In normal breast tissue cells, both P1 and P2 promoters are non- or hypo-methylated, and they are easily accessible by transcription factors such as Nrf-2. When Nrf-2 binds to its binding site in P1, transcription of TAp73 isoform will be activated. The same should apply to ΔNp73. However, since P1 is upstream of P2, the active TAp73 transcription processes will interfere with Nrf-2 binding in P2. As a result, although P2 contains three Nrf-2 binding sites, the transcription of ΔNp73 isoforms will be inhibited. This leads to high TAp73 expression and low ΔNp73 expression. When P1 and P2 promoters are hypermethylated, they are less accessible to Nrf-2. Since P1 contains three CpG islands while P2 only contains one CpG island, the methylation induced transcriptional suppression affects TAp73 expression to a larger extent. Therefore, relatively enriched Nrf-2 binding at P2 promoter will activate abundant ΔNp73 transcription, while limited binding of Nrf-2 at P1 promoter leads to restricted TAp73 transcription. As a result, under a promoter hypermethylation state, ΔNp73 will be highly expressed while TAp73 expression remains low. This will eventually contribute to cell transformation and tumorigenesis.
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Figure 6: A schematic model of dynamic regulation of TAp73 and ΔNp73 expressionA schematic model of dynamic regulation of TAp73 and ΔNp73 expression by Nrf-2-mediated transcriptional activation and CpG island methylation induced transcriptional suppression. In normal breast tissue cells, both P1 and P2 promoters are non- or hypo-methylated, and they are easily accessible by transcription factors such as Nrf-2. When Nrf-2 binds to its binding site in P1, transcription of TAp73 isoform will be activated. The same should apply to ΔNp73. However, since P1 is upstream of P2, the active TAp73 transcription processes will interfere with Nrf-2 binding in P2. As a result, although P2 contains three Nrf-2 binding sites, the transcription of ΔNp73 isoforms will be inhibited. This leads to high TAp73 expression and low ΔNp73 expression. When P1 and P2 promoters are hypermethylated, they are less accessible to Nrf-2. Since P1 contains three CpG islands while P2 only contains one CpG island, the methylation induced transcriptional suppression affects TAp73 expression to a larger extent. Therefore, relatively enriched Nrf-2 binding at P2 promoter will activate abundant ΔNp73 transcription, while limited binding of Nrf-2 at P1 promoter leads to restricted TAp73 transcription. As a result, under a promoter hypermethylation state, ΔNp73 will be highly expressed while TAp73 expression remains low. This will eventually contribute to cell transformation and tumorigenesis.

Mentions: Collectively our results suggest a model of dynamic regulation of TAp73 and ΔNp73 expression by Nrf-2-mediated transcriptional activation and CpG island methylation induced transcriptional suppression (Figure 6). In normal breast tissue cells, both P1 and P2 promoters are non- or hypo-methylated, and they are easily accessible by transcription factors such as Nrf-2. When Nrf-2 binds to its binding site in P1, transcription of TAp73 isoform will be activated. The same should apply to ΔNp73. However, since P1 is upstream of P2, the active TAp73 transcription processes will interfere with Nrf-2 binding in P2. As a result, although P2 contains three Nrf-2 binding sites, the transcription of ΔNp73 isoforms will be inhibited. This leads to high TAp73 expression and low ΔNp73 expression. When P1 and P2 promoters are hypermethylated, they are less accessible to Nrf-2. Since P1 contains three CpG islands while P2 only contains one CpG island, the methylation induced transcriptional suppression affects TAp73 expression to a larger extent. Therefore, relatively enriched Nrf-2 binding at P2 promoter will activate abundant ΔNp73 transcription, while limited binding of Nrf-2 at P1 promoter leads to restricted TAp73 transcription. As a result, under a promoter hypermethylation state, ΔNp73 will be highly expressed while TAp73 expression remains low. This will eventually contribute to cell transformation and tumorigenesis.


Transcriptional regulation of the p73 gene by Nrf-2 and promoter CpG methylation in human breast cancer.

Lai J, Nie W, Zhang W, Wang Y, Xie R, Wang Y, Gu J, Xu J, Song W, Yang F, Huang G, Cao P, Guan X - Oncotarget (2014)

A schematic model of dynamic regulation of TAp73 and ΔNp73 expressionA schematic model of dynamic regulation of TAp73 and ΔNp73 expression by Nrf-2-mediated transcriptional activation and CpG island methylation induced transcriptional suppression. In normal breast tissue cells, both P1 and P2 promoters are non- or hypo-methylated, and they are easily accessible by transcription factors such as Nrf-2. When Nrf-2 binds to its binding site in P1, transcription of TAp73 isoform will be activated. The same should apply to ΔNp73. However, since P1 is upstream of P2, the active TAp73 transcription processes will interfere with Nrf-2 binding in P2. As a result, although P2 contains three Nrf-2 binding sites, the transcription of ΔNp73 isoforms will be inhibited. This leads to high TAp73 expression and low ΔNp73 expression. When P1 and P2 promoters are hypermethylated, they are less accessible to Nrf-2. Since P1 contains three CpG islands while P2 only contains one CpG island, the methylation induced transcriptional suppression affects TAp73 expression to a larger extent. Therefore, relatively enriched Nrf-2 binding at P2 promoter will activate abundant ΔNp73 transcription, while limited binding of Nrf-2 at P1 promoter leads to restricted TAp73 transcription. As a result, under a promoter hypermethylation state, ΔNp73 will be highly expressed while TAp73 expression remains low. This will eventually contribute to cell transformation and tumorigenesis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4196172&req=5

Figure 6: A schematic model of dynamic regulation of TAp73 and ΔNp73 expressionA schematic model of dynamic regulation of TAp73 and ΔNp73 expression by Nrf-2-mediated transcriptional activation and CpG island methylation induced transcriptional suppression. In normal breast tissue cells, both P1 and P2 promoters are non- or hypo-methylated, and they are easily accessible by transcription factors such as Nrf-2. When Nrf-2 binds to its binding site in P1, transcription of TAp73 isoform will be activated. The same should apply to ΔNp73. However, since P1 is upstream of P2, the active TAp73 transcription processes will interfere with Nrf-2 binding in P2. As a result, although P2 contains three Nrf-2 binding sites, the transcription of ΔNp73 isoforms will be inhibited. This leads to high TAp73 expression and low ΔNp73 expression. When P1 and P2 promoters are hypermethylated, they are less accessible to Nrf-2. Since P1 contains three CpG islands while P2 only contains one CpG island, the methylation induced transcriptional suppression affects TAp73 expression to a larger extent. Therefore, relatively enriched Nrf-2 binding at P2 promoter will activate abundant ΔNp73 transcription, while limited binding of Nrf-2 at P1 promoter leads to restricted TAp73 transcription. As a result, under a promoter hypermethylation state, ΔNp73 will be highly expressed while TAp73 expression remains low. This will eventually contribute to cell transformation and tumorigenesis.
Mentions: Collectively our results suggest a model of dynamic regulation of TAp73 and ΔNp73 expression by Nrf-2-mediated transcriptional activation and CpG island methylation induced transcriptional suppression (Figure 6). In normal breast tissue cells, both P1 and P2 promoters are non- or hypo-methylated, and they are easily accessible by transcription factors such as Nrf-2. When Nrf-2 binds to its binding site in P1, transcription of TAp73 isoform will be activated. The same should apply to ΔNp73. However, since P1 is upstream of P2, the active TAp73 transcription processes will interfere with Nrf-2 binding in P2. As a result, although P2 contains three Nrf-2 binding sites, the transcription of ΔNp73 isoforms will be inhibited. This leads to high TAp73 expression and low ΔNp73 expression. When P1 and P2 promoters are hypermethylated, they are less accessible to Nrf-2. Since P1 contains three CpG islands while P2 only contains one CpG island, the methylation induced transcriptional suppression affects TAp73 expression to a larger extent. Therefore, relatively enriched Nrf-2 binding at P2 promoter will activate abundant ΔNp73 transcription, while limited binding of Nrf-2 at P1 promoter leads to restricted TAp73 transcription. As a result, under a promoter hypermethylation state, ΔNp73 will be highly expressed while TAp73 expression remains low. This will eventually contribute to cell transformation and tumorigenesis.

Bottom Line: However, we found Nrf-2 induced ΔNp73 expression was abolished with 5-aza-dC treatment, thus lead to a down-regulated ΔNp73 and an up-regulated TAp73 expression in breast cancer cells lines.A significant inverse correlation was found between TAp73 and ΔNp73 expression in the above tissue-array (P = 0.047) and validated in another set consisting of 128 breast cancer tumor tissue (P = 0.034).Taken together, our findings suggest that Nrf-2 and promoter methylation cooperatively govern the transcriptional regulation of p73, and unbalanced expression of TAp73 and ΔNp73 expression plays a critical role in breast cancer development.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical Oncology, Jinling Hospital, School of Medicine, Southern Medical University, Guangzhou, China; These authors contributed equally to this work.

ABSTRACT
To understand the transcriptional regulation of p73 by promoter methylation and Nrf-2 in breast carcinogenesis, ChIP assay indicated that Nrf-2 can bind to both promoters and can activate the transcription of TAp73 and ΔNp73 in MCF-7 cell line, knockdown of Nrf-2 gene resulted in an abrogation of TAp73 and ΔNp73 expression in the cells transfected with sh-Nrf-2 as well as Nrf-2 knock out mouse model. However, we found Nrf-2 induced ΔNp73 expression was abolished with 5-aza-dC treatment, thus lead to a down-regulated ΔNp73 and an up-regulated TAp73 expression in breast cancer cells lines. Consistent with this model, we detected decreased TAp73 and increased ΔNp73 expression in breast cancer tissue, along with increased TAp73 but decreased ΔNp73 expression in corresponding surrounding noncancerous tissues (NCTs) in a breast cancer tissue assay. A significant inverse correlation was found between TAp73 and ΔNp73 expression in the above tissue-array (P = 0.047) and validated in another set consisting of 128 breast cancer tumor tissue (P = 0.034). Taken together, our findings suggest that Nrf-2 and promoter methylation cooperatively govern the transcriptional regulation of p73, and unbalanced expression of TAp73 and ΔNp73 expression plays a critical role in breast cancer development.

Show MeSH
Related in: MedlinePlus