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E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells

Title
E-cadherin inhibits nuclear accumulation of Nrf2: implications for chemoresistance of cancer cells
Author
이창호
Keywords
E-cadherin; Nrf2; beta-catenin; Keap1
Issue Date
2012-03
Publisher
Company of Biologists LTD
Citation
Journal of Cell Science, 2012, 125(5), P.1284-1295
Abstract
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 beta-catenin-binding domain contributes to the inhibitory effect of E-cadherin on Nrf2. Consistently, knockdown of beta-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 beta-catenin in the interactions. Collectively, E-cadherin recruits Nrf2 through beta-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 TGF beta 1 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.
URI
http://jcs.biologists.org/content/125/5/1284http://repository.hanyang.ac.kr/handle/20.500.11754/69532
ISSN
0021-9533
DOI
10.1242/jcs.095422
Appears in Collections:
COLLEGE OF MEDICINE[S](의과대학) > MEDICINE(의학과) > Articles
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