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.