E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells.
Nrf2 has an anti-carcinogenic effect. However, an increase in Nrf2 activity is also implicated in cancer chemoresistance. A switch from E-cadherin to N-cadherin affects the transdifferentiation and metastasis of cancer cells. In view of the key role of this switch in cancer malignancy, we investigated the regulatory effect of E-cadherin ... on Nrf2. In HEK293 cells, overexpression of E-cadherin inhibited the nuclear accumulation of Nrf2, and prevented Nrf2-dependent gene induction. GST pull-down and immunocytochemical assays verified the interaction between E-cadherin and Nrf2: E-cadherin bound the C-terminus of Nrf2, but not its N-terminus, which comprises the Neh2 domain responsible for phosphorylation of Ser40. Our finding that the mutation of Ser40 to alanine in Nrf2 did not affect the ability of E-cadherin to bind Nrf2 and repress target gene transactivation suggests that E-cadherin might not disturb the phosphorylation. Studies using mutant constructs of E-cadherin suggested that the β-catenin-binding domain contributes to the inhibitory effect of E-cadherin on Nrf2. Consistently, knockdown of β-catenin attenuated not only the effect of E-cadherin binding to Nrf2, but also Keap1-dependent ubiquitylation of Nrf2, and thereby increased Nrf2 activity, supporting the involvement of β-catenin in the interactions. Collectively, E-cadherin recruits Nrf2 through β-catenin, and assists the function of Keap1 for the inhibition of nuclear localization and transcriptional activity of Nrf2. In HepG2 cells, the loss of E-cadherin by either siRNA knockdown or treatment with TGFβ1 enhanced the constitutive or inducible activity of Nrf2, implying that chemoresistance of cancer cells upon the loss of E-cadherin might be associated with Nrf2.
Mesh Terms:
Cadherins, Cell Adhesion, Cell Line, Cell Line, Tumor, Cell Transdifferentiation, Doxorubicin, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, HEK293 Cells, Hep G2 Cells, Humans, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2, Neoplasm Metastasis, Neoplasms, Phosphorylation, RNA Interference, RNA, Small Interfering, Transcription, Genetic, Transcriptional Activation, Transforming Growth Factor beta1, beta Catenin
Cadherins, Cell Adhesion, Cell Line, Cell Line, Tumor, Cell Transdifferentiation, Doxorubicin, Drug Resistance, Neoplasm, Gene Expression Regulation, Neoplastic, HEK293 Cells, Hep G2 Cells, Humans, Intracellular Signaling Peptides and Proteins, NF-E2-Related Factor 2, Neoplasm Metastasis, Neoplasms, Phosphorylation, RNA Interference, RNA, Small Interfering, Transcription, Genetic, Transcriptional Activation, Transforming Growth Factor beta1, beta Catenin
J. Cell. Sci.
Date: Mar. 01, 2012
PubMed ID: 22302998
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