Feedback loop between p66(Shc) and Nrf2 promotes lung cancer progression
Wei Du1, Yuan Jiang, Zhichao Zheng
12011 Collaborative Innovation Center of Tianjin for Medical Epigenetics, Tianjin Key Laboratory of Medical Epigenetics, Department of Immunology, Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Medical University, China.
Cancer Letters
|May 22, 2013
Summary
Epigenetic silencing of p66Shc (a protein encoded by the SHC1 gene) in cancer cells leads to increased Nrf2 expression, promoting tumor progression and cell survival.
Area of Science:
- Molecular biology
- Cancer research
- Epigenetics
Background:
- p66Shc, a protein encoded by the SHC1 gene, plays a role in cell death and metastasis suppression.
- The regulation of p66Shc in cancer cells remains largely uncharacterized.
Purpose of the Study:
- To investigate the regulatory mechanisms of p66Shc gene expression in cancer.
- To explore the relationship between p66Shc, Nrf2, and tumor progression.
Main Methods:
- Analysis of CpG methylation in the p66Shc gene promoter region in lung cancer samples and cell lines.
- Investigation of the interaction between Nrf2 and the p66Shc promoter.
- Assessment of p66Shc knockdown effects on Nrf2 expression and correlation with tumor grade.
Main Results:
- Methylation of a specific CpG site in the p66Shc gene's early post-transcriptional region correlates with p66Shc repression in lung cancer.
- The transcription factor Nrf2 binds to the methylated p66Shc promoter, but Nrf2-induced transcription requires demethylation.
- p66Shc knockdown results in positive feedback upregulation of Nrf2, which is highly expressed in tumors with low p66Shc and correlates with tumor grade.
Conclusions:
- Epigenetic repression of p66Shc via methylation is a potential driver of Nrf2 upregulation in cancer.
- This mechanism may contribute to increased cell survival and tumor progression.
- Nrf2 upregulation in tumors with low p66Shc expression suggests a role in tumor grade progression.
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