E-cadherin inhibits nuclear accumulation of Nrf2: Implications for chemoresistance of cancer cells
College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea. Journal of Cell Science
(Impact Factor: 5.43).
02/2012; 125(Pt 5):1284-95. DOI: 10.1242/jcs.095422
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.
Available from: Stuart A Rushworth
- "Since ZEB1 inhibits E-cadherin allowing EMT to occur and that E-cadherin has been shown to prevent the accumulation of NRF2 in the nucleus and that inhibition of E-cadherin results in the upregulation of NRF2 , the downregulation of miR-200c by NRF2 could potentially provide a mechanism by which NRF2 indirectly regulates E-cadherin and therefore metastasis. "
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ABSTRACT: Nuclear factor (erythroid-derived 2)-like 2 (NRF2) is a key transcription factor that regulates the expression of over a hundred cytoprotective and antioxidant genes that provide cellular protection from reactive oxygen species. Chemotherapy resistance in several cancers has been linked to dysregulation of the NRF2 signalling pathway, moreover there is growing evidence that NRF2 may contribute to tumorigenesis. MicroRNA (miRNA) are small non-coding RNA sequences that post-transcriptionally regulate mRNA sequences. In cancer pathogenesis, aberrantly expressed miRNAs can act as either tumor suppressor or oncogenic miRNA. Recent evidence has been described that identifies a number of miRNA that can be regulated by NRF2. This review outlines the importance of NRF2 in regulating miRNA, and the functional role this may have in the tumorigenesis of human malignancies and their chemotherapy resistance.
Oncotarget 08/2013; 4(8):1130-42. DOI:10.18632/oncotarget.1181 · 6.36 Impact Factor
Available from: Jennifer Batson
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ABSTRACT: The Wnt/β-catenin signalling and autophagy pathways each play important roles during development, adult tissue homeostasis and tumorigenesis. Here we identify the Wnt/β-catenin signalling pathway as a negative regulator of both basal and stress-induced autophagy. Manipulation of β-catenin expression levels in vitro and in vivo revealed that β-catenin suppresses autophagosome formation and directly represses p62/SQSTM1(encoding the autophagy adaptor p62) via TCF4. Furthermore, we show that during nutrient deprivation β-catenin is selectively degraded via the formation of a β-catenin-LC3 complex, attenuating β-catenin/TCF-driven transcription and proliferation to favour adaptation during metabolic stress. Formation of the β-catenin-LC3 complex is mediated by a W/YXXI/L motif and LC3-interacting region (LIR) in β-catenin, which is required for interaction with LC3 and non-proteasomal degradation of β-catenin. Thus, Wnt/β-catenin represses autophagy and p62 expression, while β-catenin is itself targeted for autophagic clearance in autolysosomes upon autophagy induction. These findings reveal a regulatory feedback mechanism that place β-catenin at a key cellular integration point coordinating proliferation with autophagy, with implications for targeting these pathways for cancer therapy.
The EMBO Journal 06/2013; 32(13). DOI:10.1038/emboj.2013.123 · 10.43 Impact Factor
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ABSTRACT: Nuclear factor E2-related factor 2 (Nrf2) is a transcription factor that controls the expression of a large pool of anti-oxidant and cytoprotective genes regulating cellular response to oxidative and electrophilic stress. Nrf2 is negatively regulated by Kelch-like ECH-associated protein 1 (Keap1) and, upon stimulation by an oxidative or electrophilic insult, is rapidly activated by protein stabilization. Due to its cytoprotective functions, Nrf2 has been traditionally studied in the field of chemoprevention; however, there is accumulated evidence that Keap1/Nrf2 mutations or unbalanced regulation that lead to overexpression or hyperactivation of Nrf2 may participate in tumorigenesis and be involved in chemoresistance of a wide number of solid cancers and leukemias. Besides protecting cells from reactive oxygen species, Nrf2 appears to play a direct role in cell growth control and is related to apoptosis-regulating pathways. Moreover, Nrf2 activity is connected with oncogenic kinase pathways, structural proteins, hormonal regulation, other transcription factors and epigenetic enzymes involved in the pathogenesis of different types of tumors. The aim of this review is to compile and summarize existing knowledge of the oncogenic functions of Nrf2 to provide a solid basis for its potential use as a molecular marker and pharmacological target in cancer.
Free Radical Biology and Medicine 06/2013; 65. DOI:10.1016/j.freeradbiomed.2013.06.041 · 5.74 Impact Factor
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