Decreased eIF3e Expression Can Mediate Epithelial-to-Mesenchymal Transition through Activation of the TGFβ Signaling Pathway

Desnoyers, Guillaume; Frost, Laura D.; Courteau, Lynn; Wall, Michael L.; Lewis, Stephen M.

doi:10.1158/1541-7786.mcr-14-0645

Cited by 19 publications

(29 citation statements)

References 49 publications

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“…TGFb controls important EMT markers through both canonical and noncanonical signaling in different cancers (12). Note that EMT not only is regulated through transcription but also is influenced and maintained through interconnected changes in epigenetics (13), micro-RNAs (14), long, noncoding RNAs (15), and protein synthesis (16,17).…”

Section: Introductionmentioning

confidence: 99%

A Transcriptional Program for Detecting TGFβ-Induced EMT in Cancer

Foroutan

Cursons

Hediyeh-Zadeh

et al. 2017

Molecular Cancer Research

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Most cancer deaths are due to metastasis, and epithelial-to-mesenchymal transition (EMT) plays a central role in driving cancer cell metastasis. EMT is induced by different stimuli, leading to different signaling patterns and therapeutic responses. TGFβ is one of the best-studied drivers of EMT, and many drugs are available to target this signaling pathway. A comprehensive bioinformatics approach was employed to derive a signature for TGFβ-induced EMT which can be used to score TGFβ-driven EMT in cells and clinical specimens. Considering this signature in pan-cancer cell and tumor datasets, a number of cell lines (including basal B breast cancer and cancers of the central nervous system) show evidence for TGFβ-driven EMT and carry a low mutational burden across the TGFβ signaling pathway. Furthermore, significant variation is observed in the response of high scoring cell lines to some common cancer drugs. Finally, this signature was applied to pan-cancer data from The Cancer Genome Atlas to identify tumor types with evidence of TGFβ-induced EMT. Tumor types with high scores showed significantly lower survival rates than those with low scores and also carry a lower mutational burden in the TGFβ pathway. The current transcriptomic signature demonstrates reproducible results across independent cell line and cancer datasets and identifies samples with strong mesenchymal phenotypes likely to be driven by TGFβ. The TGFβ-induced EMT signature may be useful to identify patients with mesenchymal-like tumors who could benefit from targeted therapeutics to inhibit promesenchymal TGFβ signaling and disrupt the metastatic cascade. .

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Section: Introductionmentioning

confidence: 99%

A Transcriptional Program for Detecting TGFβ-Induced EMT in Cancer

Foroutan

Cursons

Hediyeh-Zadeh

et al. 2017

Molecular Cancer Research

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“…Underexpression of eIF3h causes defects in zebrafish embryo development, suggesting that eIF3h could be directly involved in translation initiation of specific transcripts during embryogenesis (Choudhuri et al, 2013). However, our assembly data suggest that these defects could be caused by a loss of function from the inability of downstream subunits to assemble (e.g., eIF3d, e, k, and/or l; Figure 1) into eIF3, which may also be functionally equivalent to downregulating the “unassembled” subunits directly (e.g., eIF3d or e) (Desnoyers et al, 2015; Gao et al, 2015; Li et al, 2015). Alternatively, the defects could be caused by aberrant function of subcomplexes (d,e) or (k,l) unable to assemble in the absence of eIF3h (Figures 1 and 3) (Smith et al, 2013).…”

Section: Discussionmentioning

confidence: 94%

“…For example, eIF3d and e interact with CDC48 in fission yeast and could alter cell-cycle progression (Otero et al, 2010). The underexpression or truncation of eIF3e has been identified in many breast cancers (Desnoyers et al, 2015; Gillis and Lewis, 2013; Mayeur and Hershey, 2002). In our model, reduction of eIF3e levels in the cell would prevent eIF3d from assembling with eIF3, where it might localize to the nucleus as seen in certain cancers (Uhlen et al, 2005) or activate or repress the translation of certain cell-proliferation transcripts (Lee et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Assembly of eIF3 Mediated by Mutually Dependent Subunit Insertion

et al. 2016

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SUMMARY Eukaryotic initiation factor 3 (eIF3), an essential multi-protein complex involved in translation initiation, is composed of 12 tightly associated subunits in humans. While the overall structure of eIF3 is known, the mechanism of its assembly and structural consequences of dysregulation of eIF3 subunit expression seen in many cancers is largely unknown. Here we show that subunits in eIF3 assemble into eIF3 in an interdependent manner. Assembly of eIF3 is governed primarily by formation of a helical bundle, composed of helices extending C-terminally from PCI-MPN domains in eight subunits. We propose that, while the minimal subcomplex of human-like eIF3 functional for translation initiation in cells consists of subunits a, b, c, f, g, i, and m, numerous other eIF3 subcomplexes exist under circumstances of subunit over- or underexpression. Thus, eIF3 subcomplexes formed or “released” due to dysregulated subunit expression may be determining factors contributing to eIF3-related cancers.

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“…Previous research has demonstrated that epithelial-mesenchymal transition (EMT) plays a key role in the early process of the metastasis of cancer cells. This process involves the acquisition of the expression of mesenchymal molecules, such as vimentin and N-cadherin, together with the loss of epithelial cell adhesion molecules such as E-cadherin (3,4).…”

Section: Introductionmentioning

confidence: 99%

Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma

Qin

Wei

et al. 2016

Molecular Cancer Research

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Growth arrest-specific 1 (Gas1) plays a critical role in growth suppression. Previous study indicated that Gas1 was closely associated with survival in patients with colorectal cancer; however, the underlying molecular mechanism remains unclear. In this study, we sought to determine the role of Gas1 in tumorigenesis and metastasis, and elucidate the possible mechanism. First, Gas1 was determined as a negative regulator of oncogenesis and metastasis in colorectal cancer. Mechanistically, Gas1 negatively regulated the aerobic glycolysis, a process that contributed to tumor progression and metastasis by providing energy source and building blocks for macromolecule synthesis. To further consolidate the role of Gas1 in glycolysis, the impact of Gas1 in the transcription of key glycolytic enzymes for glucose utilization was examined. As expected, GLUT4, HK2, and LDHB exhibited a decreased expression pattern. Consistent with this observation, an in vivo subcutaneous xenograft mouse model also confirmed the hypothesis that Gas1 is a negative regulator of glycolysis as reflected by the decreased 18FDG uptake in PET/CT system. Moreover, Gas1 negatively regulated the AMPK/mTOR/p70S6K signaling axis, a well-established cascade that regulates malignant cancer cell behaviors including proliferation, metastasis, and aberrant cancer metabolism. In the end, it was determined that Gas1 is a transcriptional target of FOXM1, whose role in colorectal cancer has been widely studied. Taken together, these studies establish Gas1 as a negative regulator in colorectal cancer.Implications: Gas1 suppresses cell proliferation, invasion, and aerobic glycolysis of colorectal cancer both in vitro and in vivo. Mechanistically, Gas1 inhibited EMT and the Warburg effect via AMPK/mTOR/p70S6K signaling, and Gas1 itself was directly regulated by the transcription factor FOXM1.

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Decreased eIF3e Expression Can Mediate Epithelial-to-Mesenchymal Transition through Activation of the TGFβ Signaling Pathway

Cited by 19 publications

References 49 publications

A Transcriptional Program for Detecting TGFβ-Induced EMT in Cancer

A Transcriptional Program for Detecting TGFβ-Induced EMT in Cancer

Assembly of eIF3 Mediated by Mutually Dependent Subunit Insertion

Gas1 Inhibits Metastatic and Metabolic Phenotypes in Colorectal Carcinoma

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