Transcriptional regulation of the p73 gene by Nrf-2 and promoter CpG methylation in human breast cancer
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Jing Lai1,*, Weiwei Nie1,*, Wenwen Zhang2,*, Yucai Wang3, Ruilian Xie1, Yanru Wang1, Jun Gu4, Jing Xu2, Wei Song1, Fang Yang2, Guichun Huang2, Peng Cao5 and Xiaoxiang Guan1,2
1 Department of Medical Oncology, Jinling Hospital, School of Medicine, Southern Medical University, Guangzhou, China
2 Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
3 Department of Medicine, Rutgers New Jersey Medical School, Newark, NJ, USA
4 Department of General Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, China
5 Laboratory of Cellular and Molecular Biology, Jiangsu Province Institute of Chinese Medicine, Nanjing, China
* These authors contributed equally to this work
Xiaoxiang Guan, email:
Keywords: breast cancer; TAp73; ΔΝp73; Nrf-2; methylation; transcription
Received: June 18, 2014 Accepted: July 16, 2014 Published: July 17, 2014
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 ΔΝp73 in MCF-7 cell line, knockdown of Nrf-2 gene resulted in an abrogation of TAp73 and ΔΝp73 expression in the cells transfected with sh-Nrf-2 as well as Nrf-2 knock out mouse model. However, we found Nrf-2 induced ΔΝp73 expression was abolished with 5-aza-dC treatment, thus lead to a down-regulated ΔΝp73 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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