Abstract
The epithelial-to-mesenchymal transition (EMT) program is crucial for the epithelial cancer progression and fibrotic diseases. Our previous work has demonstrated that p66Shc, a focal adhesion-associated adaptor protein, is frequently downregulated in lung cancers and its depletion promotes metastasis behavior through anoikis resistance. However, mechanism underlying loss of p66Shc and EMT response is not fully understood. Here, we showed that p66Shc deficiency enhanced the expression of ZEB1, the known mesenchymal transcription factor and consequently increased Vimentin, and decreased epithelial markers of E-cadherin and β-catenin. p66Shc depletion also increased cell invasion and migration. In addition, ChIP and luciferase assays showed that these effects were directly mediated by ZEB1 repression of p66Shc promoter. Thus, our findings define a critical role of p66Shc in the suppression of fibrotic EMT response with a negative feedback loop between p66Shc and ZEB1 in lung epithelial cancer cells.
Highlights
Owing to its high metastasis, lung cancer is clinically one of the leading causes of cancer-related death worldwide.[1]
We report here that metastasis suppressor p66Shc expression is dependent on cell density in lung cancer cells and represses the oncogenic epithelial-to-mesenchymal transition (EMT)-activator zinc-finger E-box-binding homeobox 1 (ZEB1)
A similar cell morphology change with Transforming growth factor-β1 (TGFβ1) treatment was observed in Figure 1c, left panel, when compared with the non-treated control cells (Figure 1c, right panel). β-catenin immunostaining showed its dissociation from plasma and its relocalization to the cytosol and nucleus in p66Shc-depleted cells (Figure 1c, left panel), confirming that p66Shc was involved in fibrotic EMT response with cell morphological change
Summary
Owing to its high metastasis, lung cancer is clinically one of the leading causes of cancer-related death worldwide.[1]. The mammal adaptor proteins Shc[1] (p66Shc, p52Shc and p46Shc) share a C-terminal Src homology 2 domain, a central collagen-homologous (CH1) domain and an N-terminal phosphotyrosine-binding domain and have N termini of different lengths.[16] Despite their high structural similarity, p66Shc and p52Shc/p46Shc are involved in multiple signaling mechanisms to support diversity in cell homeostasis.[17] Of the two Shc[1] transcripts and three isoforms, p66Shc activates pro-apoptosis in response to oxidative stress and functions as a critical regulator of longevity in mice.[18,19] Structurally, an additional 110-amino-acid CH2 domain of p66Shc at the amino terminal differs from p52Shc and p46Shc isoforms.[18] We have previously shown that p66Shc is a focal adhesion-associated protein, permits anchorage sensing through a RhoA-dependent mechanosensory test of the environment, mediates anoikis in epithelial cells, and has an important role in preventing solid cancer metastasis.[20] In addition, a stress related transcription factor Nrf[2] binds to p66Shc promoter and promotes p66Shc transcription, which links to reactive oxygen species (ROS) control and tumorigenesis.[19,21] Loss of p66Shc expression
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