Feedback loop between p66(Shc) and Nrf2 promotes lung cancer progression.

p66(Shc), one of the SHC1 gene encoding proteins, promotes cell death and reports cell anchorage status, mediating anoikis in vitro and functioning as a metastasis suppressor in vivo. However, very little is known about p66(Shc) gene regulation in cancer cells. Here, we show that methylation of a specific CpG site in the early post-transcriptional region correlates with p66(Shc) repression in clinical human lung cancer samples and cancer cell lines. We also find that the stress related transcription factor Nrf2 associates with p66(Shc) gene promoter in the methylated region, and promotes p66(Shc) transcription. However, p66(Shc) induction by Nrf2 requires demethylation of the Nrf2 binding site in p66(Shc) promoter. Knock-down of p66(Shc) leads to a positive feedback upregulation of Nrf2 expression and accordingly, Nrf2 is found to be highly expressed in tumors with low p66(Shc) expression. Further, Nrf2 expression level positively correlates with tumor grade of patients. Thus, we propose that epigenetic repression of p66(Shc) in cancer cells might be a key factor leading to Nrf2 upregulation, increased cell survival, and tumor progression.