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Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers.
Peng X, Chen Z, Farshidfar F, Xu X, Lorenzi PL, Wang Y, Cheng F, Tan L, Mojumdar K, Du D, Ge Z, Li J, Thomas GV, Birsoy K, Liu L, Zhang H, Zhao Z, Marchand C, Weinstein JN, Cancer Genome Atlas Research Network, Bathe OF, Liang H
(2018) Cell Rep 23: 255-269.e4
MeSH Terms: Cell Line, Tumor, Core Binding Factor Alpha 2 Subunit, Drug Resistance, Neoplasm, HEK293 Cells, Humans, Metabolic Networks and Pathways, Neoplasms, Snail Family Transcription Factors, Transcriptome
Show Abstract · Added October 30, 2019
Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1-master regulators of carbohydrate metabolic subtypes-modulates metabolic activity and drug sensitivity. Our study provides a system-level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility.
Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
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MeSH Terms
LASP-1: a nuclear hub for the UHRF1-DNMT1-G9a-Snail1 complex.
Duvall-Noelle N, Karwandyar A, Richmond A, Raman D
(2016) Oncogene 35: 1122-33
MeSH Terms: Active Transport, Cell Nucleus, Adaptor Proteins, Signal Transducing, Breast Neoplasms, CCAAT-Enhancer-Binding Proteins, Cell Line, Tumor, Chemokine CXCL12, Cytoskeletal Proteins, DNA (Cytosine-5-)-Methyltransferase 1, DNA (Cytosine-5-)-Methyltransferases, Epigenesis, Genetic, Gene Knockdown Techniques, Heterocyclic Compounds, Histocompatibility Antigens, Histone-Lysine N-Methyltransferase, Histones, Humans, LIM Domain Proteins, Prognosis, Proteomics, Signal Transduction, Snail Family Transcription Factors, Transcription Factors, Tumor Microenvironment
Show Abstract · Added May 20, 2015
Nuclear LASP-1 (LIM and SH3 protein-1) has a direct correlation with overall survival of breast cancer patients. In this study, immunohistochemical analysis of a human breast TMA showed that LASP-1 is absent in normal human breast epithelium but the expression increases with malignancy and is highly nuclear in aggressive breast cancer. We investigated whether the chemokines and growth factors present in the tumor microenvironment could trigger nuclear translocation of LASP-1.Treatment of human breast cancer cells with CXCL12, EGF and HRG, and HMEC-CXCR2 cells with CXCL8 facilitated nuclear shuttling of LASP-1. Data from the biochemical analysis of the nuclear and cytosolic fractions further confirmed the nuclear translocation of LASP-1 upon chemokine and growth factor treatment. CXCL12-dependent nuclear import of LASP-1 could be blocked by CXCR4 antagonist, AMD-3100. Knock down of LASP-1 resulted in alterations in gene expression leading to an increased level of cell-junction and extracellular matrix proteins and an altered cytokine secretory profile. Three-dimensional cultures of human breast cancer cells on Matrigel revealed an altered colony growth, morphology and arborization pattern in LASP-1 knockdown cells. Functional analysis of the LASP-1 knockdown cells revealed increased adhesion to collagen IV and decreased invasion through the Matrigel. Proteomic analysis of immunoprecipitates of LASP-1 and subsequent validation approaches revealed that LASP-1 associated with the epigenetic machinery especially UHRF1, DNMT1, G9a and the transcription factor Snail1. Interestingly, LASP-1 associated with UHRF1, G9a, Snail1 and di- and tri-methylated histoneH3 in a CXCL12-dependent manner based on immunoprecipitation and proximity ligation assays. LASP-1 also directly bound to Snail1 which may stabilize Snail1. Thus, nuclear LASP-1 appears to functionally serve as a hub for the epigenetic machinery.
2 Communities
2 Members
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23 MeSH Terms
Helicobacter pylori targets cancer-associated apical-junctional constituents in gastroids and gastric epithelial cells.
Wroblewski LE, Piazuelo MB, Chaturvedi R, Schumacher M, Aihara E, Feng R, Noto JM, Delgado A, Israel DA, Zavros Y, Montrose MH, Shroyer N, Correa P, Wilson KT, Peek RM
(2015) Gut 64: 720-30
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Claudins, Coculture Techniques, Epithelial Cells, Gastric Mucosa, Helicobacter Infections, Helicobacter pylori, Humans, Mice, Inbred C57BL, Snail Family Transcription Factors, Transcription Factors, beta Catenin
Show Abstract · Added January 20, 2015
OBJECTIVE - Helicobacter pylori strains that express the oncoprotein CagA augment risk for gastric cancer. However, the precise mechanisms through which cag(+) strains heighten cancer risk have not been fully delineated and model systems that recapitulate the gastric niche are critical for understanding pathogenesis. Gastroids are three-dimensional organ-like structures that provide unique opportunities to study host-H. pylori interactions in a preclinical model. We used gastroids to inform and direct in vitro studies to define mechanisms through which H. pylori modulates expression of the cancer-associated tight junction protein claudin-7.
DESIGN - Gastroids were infected by luminal microinjection, and MKN28 gastric epithelial cells were cocultured with H. pylori wild-type cag(+) strains or isogenic mutants. β-catenin, claudin-7 and snail localisation was determined by immunocytochemistry. Proliferation was assessed using 5-ethynyl-2'-deoxyuridine, and levels of claudin-7 and snail were determined by western blot and flow cytometry.
RESULTS - Gastroids developed into a self-organising differentiation axis and H. pylori induced mislocalisation of claudin-7 and increased proliferation in a CagA- and β-catenin-dependent manner. In MKN28 cells, H pylori-induced suppression of claudin-7 was regulated by β-catenin and snail. Similarly, snail expression was increased and claudin-7 levels were decreased among H. pylori-infected individuals.
CONCLUSIONS - H. pylori increase proliferation in a strain-specific manner in a novel gastroid system. H. pylori also alter expression and localisation of claudin-7 in gastroids and human epithelial cells, which is mediated by β-catenin and snail activation. These data provide new insights into molecular interactions with carcinogenic potential that occur between H. pylori and epithelial cells within the gastric niche.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
0 Communities
4 Members
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14 MeSH Terms
Slug regulates E-cadherin repression via p19Arf in prostate tumorigenesis.
Xie Y, Liu S, Lu W, Yang Q, Williams KD, Binhazim AA, Carver BS, Matusik RJ, Chen Z
(2014) Mol Oncol 8: 1355-64
MeSH Terms: Animals, Cadherins, Cyclin-Dependent Kinase Inhibitor p16, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Gene Knockout Techniques, Humans, Male, Mice, Prostate, Prostatic Neoplasms, SUMO-1 Protein, Snail Family Transcription Factors, Transcription Factors
Show Abstract · Added January 20, 2015
SLUG represses E-cadherin to promote epithelial-mesenchymal transition (EMT) in various cancers. Mechanisms that regulate SLUG/E-cadherin pathway remain poorly understood, especially during tumorigenesis in vivo. Here we report that p19(Arf) (p14(ARF) in human) stabilizes Slug to inhibit E-cadherin in prostate cancer mouse models. Inactivation of p19(Arf) reduces Slug levels, resulting in increased E-cadherin expression and delaying the onset and progression of prostate cancer in Pten/Trp53 double null mice. Mechanistically, p14(ARF) stabilizes SLUG through increased sumoylation at lysine residue 192. Importantly, levels of SLUG and p14(ARF) are positively correlated in human prostate cancer specimens. These data demonstrated that ARF modulates the SLUG/E-cadherin signaling axis for augmenting prostate tumorigenesis in vivo, revealing a novel paradigm where the oncogenic functions of SLUG require ARF to target E-cadherin in prostate cancer. Collectively, our findings further support that ARF has dual tumor suppressive/oncogenic roles in cancers in a context-dependent manner.
Copyright © 2014 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.
1 Communities
1 Members
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14 MeSH Terms
The collagen receptor discoidin domain receptor 2 stabilizes SNAIL1 to facilitate breast cancer metastasis.
Zhang K, Corsa CA, Ponik SM, Prior JL, Piwnica-Worms D, Eliceiri KW, Keely PJ, Longmore GD
(2013) Nat Cell Biol 15: 677-87
MeSH Terms: Animals, Breast Neoplasms, Cadherins, Carcinoma, Ductal, Breast, Cell Line, Tumor, Cell Movement, Cell Proliferation, Discoidin Domain Receptors, Epithelial-Mesenchymal Transition, Female, HEK293 Cells, Humans, Mice, Mice, Inbred BALB C, Mitogen-Activated Protein Kinase 1, Neoplasm Invasiveness, Neoplasm Metastasis, Phosphorylation, RNA Interference, RNA, Small Interfering, Receptor Protein-Tyrosine Kinases, Receptors, Collagen, Receptors, Mitogen, Signal Transduction, Snail Family Transcription Factors, Transcription Factors
Show Abstract · Added July 31, 2013
Increased stromal collagen deposition in human breast tumours correlates with metastases. We show that activation of the collagen I receptor DDR2 (discoidin domain receptor 2) regulates SNAIL1 stability by stimulating ERK2 activity, in a Src-dependent manner. Activated ERK2 directly phosphorylates SNAIL1, leading to SNAIL1 nuclear accumulation, reduced ubiquitylation and increased protein half-life. DDR2-mediated stabilization of SNAIL1 promotes breast cancer cell invasion and migration in vitro, and metastasis in vivo. DDR2 expression was observed in most human invasive ductal breast carcinomas studied, and was associated with nuclear SNAIL1 and absence of E-cadherin expression. We propose that DDR2 maintains SNAIL1 level and activity in tumour cells that have undergone epithelial-mesenchymal transition (EMT), thereby facilitating continued tumour cell invasion through collagen-I-rich extracellular matrices by sustaining the EMT phenotype. As such, DDR2 could be an RTK (receptor tyrosine kinase) target for the treatment of breast cancer metastasis.
1 Communities
0 Members
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26 MeSH Terms
Signaling between transforming growth factor β (TGF-β) and transcription factor SNAI2 represses expression of microRNA miR-203 to promote epithelial-mesenchymal transition and tumor metastasis.
Ding X, Park SI, McCauley LK, Wang CY
(2013) J Biol Chem 288: 10241-53
MeSH Terms: Animals, Breast Neoplasms, Cell Line, Tumor, Dogs, Epithelial-Mesenchymal Transition, Female, Gene Expression Regulation, Neoplastic, Humans, MicroRNAs, Neoplasm Metastasis, Neoplasm Proteins, RNA, Neoplasm, Signal Transduction, Snail Family Transcription Factors, Transcription Factors, Transforming Growth Factor beta
Show Abstract · Added March 5, 2014
TGF-β promotes tumor invasion and metastasis by inducing an epithelial-mesenchymal transition (EMT). Understanding the molecular and epigenetic mechanisms by which TGF-β induces EMT may facilitate the development of new therapeutic strategies for metastasis. Here, we report that TGF-β induced SNAI2 to promote EMT by repressing miR-203. Although miR-203 targeted SNAI2, SNAI2 induced by TGF-β could directly bind to the miR-203 promoter to inhibit its transcription. SNAI2 and miR-203 formed a double negative feedback loop to inhibit each other's expression, thereby controlling EMT. Moreover, we found that miR-203 was significantly down-regulated in highly metastatic breast cancer cells. The restoration of miR-203 in highly metastatic breast cancer cells inhibited tumor cell invasion in vitro and lung metastatic colonization in vivo by repressing SNAI2. Taken together, our results suggest that the SNAI2 and miR-203 regulatory loop plays important roles in EMT and tumor metastasis.
0 Communities
1 Members
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16 MeSH Terms
Smoking induces epithelial-to-mesenchymal transition in non-small cell lung cancer through HDAC-mediated downregulation of E-cadherin.
Nagathihalli NS, Massion PP, Gonzalez AL, Lu P, Datta PK
(2012) Mol Cancer Ther 11: 2362-72
MeSH Terms: Acetylation, Antigens, CD, Benzamides, Cadherins, Carcinoma, Non-Small-Cell Lung, Cell Movement, Down-Regulation, Epigenesis, Genetic, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Histone Deacetylase Inhibitors, Histone Deacetylases, Humans, Lung Neoplasms, Lymphoid Enhancer-Binding Factor 1, Neoplasm Invasiveness, Promoter Regions, Genetic, Pyridines, Smoking, Snail Family Transcription Factors, Survival Analysis, Transcription Factors, Transcription, Genetic
Show Abstract · Added June 14, 2013
Epidemiological studies have shown that most cases of lung cancers (85%-90%) are directly attributable to tobacco smoking. Although association between cigarette smoking and lung cancer is well documented, surprisingly little is known about the molecular mechanisms of how smoking is involved in epithelial-to-mesenchymal transition (EMT) through epigenetic changes. Here, we show that lung cancer patients with a smoking history have low E-cadherin levels and loss of E-cadherin is a poor prognostic factor in smokers. Moreover, the downregulation of E-cadherin correlates with the number of pack years. In an attempt to determine the role of long-term cigarette smoking on EMT, we observed that treatment of lung cell lines with cigarette smoke condensate (CSC) induces EMT through downregulation of epithelial markers, including E-cadherin and upregulation of mesenchymal markers. CSC decreases E-cadherin expression at the transcriptional level through upregulation of LEF1 and Slug, and knockdown of these two proteins increases E-cadherin expression. Importantly, chromatin immunoprecipitation assays suggest that LEF-1 and Slug binding to E-cadherin promoter is important for CSC-mediated downregulation of E-cadherin. The histone deacetylase (HDAC) inhibitor MS-275 reverses CSC-induced EMT, migration, and invasion through the restoration of E-cadherin expression. These results suggest that recruitment of HDACs by transcriptional repressors LEF-1 and Slug is responsible for E-cadherin suppression and EMT in cigarette smokers and provide a potential drug target toward the treatment of lung cancer.
©2012 AACR.
0 Communities
2 Members
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23 MeSH Terms
Loss of glutathione S-transferase A4 accelerates obstruction-induced tubule damage and renal fibrosis.
Liang A, Wang Y, Woodard LE, Wilson MH, Sharma R, Awasthi YC, Du J, Mitch WE, Cheng J
(2012) J Pathol 228: 448-58
MeSH Terms: Aldehydes, Animals, Autophagy, Cells, Cultured, DNA Transposable Elements, Fibroblasts, Fibrosis, Glutathione Transferase, Intercellular Junctions, Kidney Tubules, Lipid Peroxidation, Male, Mice, Knockout, RNA, Messenger, Snail Family Transcription Factors, Transcription Factors, Ureteral Obstruction
Show Abstract · Added December 8, 2017
Glutathione transferase isozyme A4 (GSTA4) exhibits high catalytic efficiency to metabolize 4-hydroxynonenal (4-HNE), a highly reactive lipid peroxidation product that has been implicated in the pathogenesis of various chronic diseases. We investigated the role of 4-HNE in the mechanisms of unilateral ureteral obstruction (UUO)-induced fibrosis and its modulation by GSTA4-4 in a mouse model. Our data indicate that after UUO, accumulation of 4-HNE and its adducts were increased in renal tissues, with a concomitant decrease in the expression of GSTA4-4 in mice. As compared to wild-type (WT) mice, UUO caused an increased expression of fibroblast markers in the interstitium of GSTA4 KO mice. Additionally, increased autophagy and tubular cell damage were more severe in UUO-treated GSTA4 KO mice than in WT mice. Furthermore, GSK-3β phosphorylation and expression of Snail, a regulator of E-cadherin and Occludin, was found to be significantly higher in UUO-inflicted GSTA4 KO mice. GSTA4 over-expression prevented 4-HNE-induced autophagy activation, tubular cell damage and Snail nuclear translocation in vitro. The effects of long-term expression of GSTA4 in restoration of UUO-induced damage in mice with the GSTA4 inducible transposon system indicated that release of obstruction after 3 days of UUO resulted in the attenuation of interstitial SMAα and collagen I expression. This transposon-delivered GSTA4 expression also suppressed UUO-induced loss of tubular cell junction markers and autophagy activation. Together, these results indicate that 4-HNE significantly contributes to the mechanisms of tubule injury and fibrosis and that these effects can be inhibited by the enhanced expression of GSTA4-4.
Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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1 Members
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17 MeSH Terms
High motility of triple-negative breast cancer cells is due to repression of plakoglobin gene by metastasis modulator protein SLUG.
Bailey CK, Mittal MK, Misra S, Chaudhuri G
(2012) J Biol Chem 287: 19472-86
MeSH Terms: Actin Cytoskeleton, Breast Neoplasms, Cell Line, Tumor, Cell Movement, Desmoplakins, Female, Gene Expression Regulation, Neoplastic, Humans, Neoplasm Metastasis, Neoplasm Proteins, Promoter Regions, Genetic, RNA, Messenger, RNA, Neoplasm, Snail Family Transcription Factors, Transcription Factors, gamma Catenin
Show Abstract · Added July 10, 2015
One of highly pathogenic breast cancer cell types are the triple negative (negative in the expression of estrogen, progesterone, and ERBB2 receptors) breast cancer cells. These cells are highly motile and metastatic and are characterized by high levels of the metastasis regulator protein SLUG. Using isogenic breast cancer cell systems we have shown here that high motility of these cells is directly correlated with the levels of the SLUG in these cells. Because epithelial/mesenchymal cell motility is known to be negatively regulated by the catenin protein plakoglobin, we postulated that the transcriptional repressor protein SLUG increases the motility of the aggressive breast cancer cells through the knockdown of the transcription of the plakoglobin gene. We found that SLUG inhibits the expression of plakoglobin gene directly in these cells. Overexpression of SLUG in the SLUG-deficient cancer cells significantly decreased the levels of mRNA and protein of plakoglobin. On the contrary, knockdown of SLUG in SLUG-high cancer cells elevated the levels of plakoglobin. Blocking of SLUG function with a double-stranded DNA decoy that competes with the E2-box binding of SLUG also increased the levels of plakoglobin mRNA, protein, and promoter activity in the SLUG-high triple negative breast cancer cells. Overexpression of SLUG in the SLUG-deficient cells elevated the motility of these cells. Knockdown of plakoglobin in these low motility non-invasive breast cancer cells rearranged the actin filaments and increased the motility of these cells. Forced expression of plakoglobin in SLUG-high cells had the reverse effects on cellular motility. This study thus implicates SLUG-induced repression of plakoglobin as a motility determinant in highly disseminating breast cancer.
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16 MeSH Terms
Nfatc1 coordinates valve endocardial cell lineage development required for heart valve formation.
Wu B, Wang Y, Lui W, Langworthy M, Tompkins KL, Hatzopoulos AK, Baldwin HS, Zhou B
(2011) Circ Res 109: 183-92
MeSH Terms: Animals, Cell Lineage, Endocardium, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Developmental, Heart Valves, Mice, Morphogenesis, NFATC Transcription Factors, Organogenesis, Snail Family Transcription Factors, Transcription Factors, Transcription, Genetic
Show Abstract · Added November 13, 2012
RATIONALE - Formation of heart valves requires early endocardial to mesenchymal transformation (EMT) to generate valve mesenchyme and subsequent endocardial cell proliferation to elongate valve leaflets. Nfatc1 (nuclear factor of activated T cells, cytoplasmic 1) is highly expressed in valve endocardial cells and is required for normal valve formation, but its role in the fate of valve endocardial cells during valve development is unknown.
OBJECTIVE - Our aim was to investigate the function of Nfatc1 in cell-fate decision making by valve endocardial cells during EMT and early valve elongation.
METHODS AND RESULTS - Nfatc1 transcription enhancer was used to generate a novel valve endocardial cell-specific Cre mouse line for fate-mapping analyses of valve endocardial cells. The results demonstrate that a subpopulation of valve endocardial cells marked by the Nfatc1 enhancer do not undergo EMT. Instead, these cells remain within the endocardium as a proliferative population to support valve leaflet extension. In contrast, loss of Nfatc1 function leads to enhanced EMT and decreased proliferation of valve endocardium and mesenchyme. The results of blastocyst complementation assays show that Nfatc1 inhibits EMT in a cell-autonomous manner. We further reveal by gene expression studies that Nfatc1 suppresses transcription of Snail1 and Snail2, the key transcriptional factors for initiation of EMT.
CONCLUSIONS - These results show that Nfatc1 regulates the cell-fate decision making of valve endocardial cells during valve development and coordinates EMT and valve elongation by allocating endocardial cells to the 2 morphological events essential for valve development.
1 Communities
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13 MeSH Terms