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The transcription factors Slug (SNAI2) and Snail (SNAI1) regulate phospholipase D (PLD) promoter in opposite ways towards cancer cell invasion.

ABSTRACT: Slug (SNAI2) and Snail (SNAI1) are master regulatory transcription factors for organogenesis and wound healing, and they are involved in the epithelial to mesenchymal transition (EMT) of cancer cells. We found that the activity of phospholipase D isoform 2 (PLD2) is highly increased in cancers with larger size and poor prognosis (MDA-MB-231 versus MCF-7 cells), so we determined if Snail or Slug were responsible for PLD2 gene transcription regulation. Unexpectedly, we found that PLD2 expression was positively regulated by Slug but negatively regulated by Snail. The differential effects are amplified in breast cancer cells over normal cells and with MDA-MB-231 more robustly than MCF-7. Slug putatively binds to the PLD2 promoter and transactivates it, which is negated when Slug and Snail compete with each other. Meanwhile, PLD2 has a negative effect on Snail expression and a positive effect on Slug, thus closing a feedback loop between the lipase and the transcription factors. Further, PA, the product of PLD2 enzymatic reaction, has profound effects on its own and it further regulates the transcription factors. Thus, we show for the first time that the overexpressed PLD2 in human breast tumors is regulated by Slug and Snail transcription factors. The newly uncovered feedback loops in highly invasive cancer cells have important implications in the process of EMT.

SUBMITTER: Ganesan R

PROVIDER: S-EPMC4870114 | biostudies-other | 2016 May

REPOSITORIES: biostudies-other

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Inhibiting interactions of lysine demethylase LSD1 with snail/slug blocks cancer cell invasion.

Project description:The process of epithelial-mesenchymal transition (EMT) which is required for cancer cell invasion is regulated by a family of E-box-binding transcription repressors, which include Snail (SNAIL1) and Slug (SNAI2). Snail appears to repress the expression of the EMT marker E-cadherin by epigenetic mechanisms dependent on the interaction of its N-terminal SNAG domain with chromatin-modifying proteins including lysine-specific demethylase 1 (LSD1/KDM1A). We assessed whether blocking Snail/Slug-LSD1 interaction by treatment with Parnate, an enzymatic inhibitor of LSD1, or TAT-SNAG, a cell-permeable peptide corresponding to the SNAG domain of Slug, suppresses the motility and invasiveness of cancer cells of different origin and genetic background. We show here that either treatment blocked Slug-dependent repression of the E-cadherin promoter and inhibited the motility and invasion of tumor cell lines without any effect on their proliferation. These effects correlated with induction of epithelial and repression of mesenchymal markers and were phenocopied by LSD1 or Slug downregulation. Parnate treatment also inhibited bone marrow homing/engraftment of Slug-expressing K562 cells. Together, these studies support the concept that targeting Snail/Slug-dependent transcription repression complexes may lead to the development of novel drugs selectively inhibiting the invasive potential of cancer cells.

| S-EPMC3537890 | biostudies-literature

Snail/Slug-YAP/TAZ complexes cooperatively regulate mesenchymal stem cell function and bone formation.

Project description:Snail and Slug are zinc-finger transcription factors that play key roles in directing the epithelial-mesenchymal transition (EMT) programs associated with normal development as well as disease progression. More recent work suggests that these EMT-associated transcription factors also modulate the function of both embryonic and adult stem cells. Interestingly, YAP and TAZ, the co-transcriptional effectors of the Hippo pathway, likewise play an important role in stem cell self-renewal and lineage commitment. While direct intersections between the Snail/Slug and Hippo pathways have not been described previously, we recently described an unexpected cooperative interaction between Snail/Slug and YAP/TAZ that controls the self-renewal and differentiation properties of bone marrow-derived mesenchymal stem cells (MSCs), a cell population critical to bone development. Additional studies revealed that both Snail and Slug are able to form binary complexes with either YAP or TAZ that, together, control YAP/TAZ transcriptional activity and function throughout mouse development. Given the more recent observations that MSC-like cell populations are found in association throughout the vasculature where they participate in tissue regeneration, fibrosis and cancer, the Snail/Slug-YAP/TAZ axis is well-positioned to regulate global stem cell function in health and disease.

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The invasion promoter Slug is a critical cell cycle regulator

Project description:Background: The well-characterized function of the transcriptional repressor, Slug, is to promote EMT and tumor invasion/metastasis by down-regulating E-cadherin expression. In this study, we investigated the significance of Slug during the S phase. Method: Slug mRNA expression was isolated from thymidine-arrested CL1-5/AS2neo (control) and CL1-5/AS2neo-Slug-WT stable cells. The Agilent oligonucleotide microarray analysis was performed to identify Slug downstream genes. Results: Overexpression of Slug inhibited lung [3H]-thymidine incorporation and delayed S phase progression. By using Agilent microarray we have identified panel of genes altered by Slug overexpression. Slug can down-regulate target genes about cell cycle networks for DNA replication, DNA replication checkpoint and genomic stability, such as TOP1, ORC4, RFC3, and Rad17. Conclusions: the multifaceted role of Slug in cancer progression by controlling the epithelial-mesenchymal transition and genome stability. Two-condition experiment, Vector vs. Slug overexpression cells. The cDNAs encoding full-length human Slug were amplified and subcloned into lentiviral pLKO_AS2.neo which generated full-length Slug. Vector control or Slug lentivirus were transduced into CL1-5 cells and Gentamycin was used to select stable cells.

2012-02-09 | E-GEOD-35617 | biostudies-arrayexpress

The invasion promoter Slug is a critical cell cycle regulator

2012-02-09 | GSE35617 | GEO

AP-2? inhibits hepatocellular carcinoma invasion and metastasis through Slug and Snail to suppress epithelial-mesenchymal transition.

Project description:Transcription factor AP-2? plays an important role in human cancer, but its clinical significance in hepatocellular carcinogenesis is largely unknown. Methods: AP-2? expression was detected in human hepatocellular cancer (HCC) tissues and cell lines. The effects of AP-2? on HCC proliferation, migration, invasion, tumor formation and metastasis were evaluated by MTT, colony formation and transwell assays in vitro and mouse experiments in vivo. The association between AP-2? and miR-27a/EMT markers in HCC cell lines and tissues was analyzed. Results: AP-2? expression was decreased in HCC tissues and cell lines. Reduced expression of AP-2? was significantly associated with more advanced tumor stages and larger tumor sizes. The overexpression of AP-2? reduced HCC proliferation, migration, invasion, tumor formation and metastasis in vitro and in vivo. Additionally, AP-2? overexpression increased the sensitivity of HCC cells to cisplatin. Moreover, AP-2? modulates the levels of EMT markers through Slug and Snail in HCC cell lines and tissues. Furthermore, oncogenic miR-27a inhibits AP-2? expression by binding to the AP-2? 3' untranslated region (UTR) and reverses the tumor suppressive role of AP-2?. Conclusion: These results suggested that AP-2? is lowly expressed in HCC by inhibiting EMT signaling to regulate HCC cell growth and migration. Therefore, AP-2? in the novel miR-27a/AP-2?/Slug/EMT regulatory axis enhances the chemotherapeutic drug sensitivity of HCC and might represent a potential target for evaluating the treatment and prognosis of human HCC.

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Directed mutagenesis of the Rickettsia prowazekii pld gene encoding phospholipase D.

Project description:Rickettsia prowazekii, the causative agent of epidemic typhus, is an obligately intracytoplasmic bacterium, a lifestyle that imposes significant barriers to genetic manipulation. The key to understanding how this unique bacterium evades host immunity is the mutagenesis of selected genes hypothesized to be involved in virulence. The R. prowazekii pld gene, encoding a protein with phospholipase D activity, has been associated with phagosomal escape. To demonstrate the feasibility of site-directed knockout mutagenesis of rickettsial genes and to generate a nonrevertible vaccine strain, we utilized homologous recombination to generate a pld mutant of the virulent R. prowazekii strain Madrid Evir. Using linear DNA for transformation, a double-crossover event resulted in the replacement of the rickettsial wild-type gene with a partially deleted pld gene. Linear DNA was used to prevent potentially revertible single-crossover events resulting in plasmid insertion. Southern blot and PCR analyses were used to confirm the presence of the desired mutation and to demonstrate clonality. While no phenotypic differences were observed between the mutant and wild-type strains when grown in tissue culture, the pld mutant exhibited attenuated virulence in the guinea pig model. In addition, animals immunized with the mutant strain were protected against subsequent challenge with the virulent Breinl strain, suggesting that this transformant could serve as a nonrevertible, attenuated vaccine strain. This study demonstrates the feasibility of generating site-directed rickettsial gene mutants, providing a new tool for understanding rickettsial biology and furthering advances in the prevention of epidemic typhus.

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Inhibition of Migration, Invasion and Drug Resistance of Pancreatic Adenocarcinoma Cells - Role of Snail, Slug and Twist and Small Molecule Inhibitors.

Project description:Purpose:The main purpose of this study is to demonstrate the effects of epithelial to mesenchymal transition activating transcription factor silencing (EMT-ATF silencing) on migration, invasion, drug resistance and tumor-forming abilities of various pancreatic cancer cell lines. Additionally, the contribution of small molecule inhibitors of EMT (SD-208 and CX4945) to the effects of gene silencing was evaluated. Methods:EMT activating transcription factors "Snail, Slug and Twist" were silenced by short hairpins on Panc-1, MIA PaCa-2, BxPC-3, and AsPC-1 pancreatic cancer cell lines. The changes in migration, invasion, laminin attachment, cancer stem-like cell properties and tumor-forming abilities were investigated. Chemosensitivity assays and small molecule inhibitors of EMT were applied to the metastatic pancreatic cancer cell line AsPC-1. Results:EMT-ATF silencing reduced EMT and stem cell-like characteristics of pancreatic cancer cell lines. Following EMT-ATF silencing amongst the four PC cell lines, AsPC-1 showed the best response and was chosen for further chemoresistance and combinational therapy applications. EMT downregulated AsPC-1 cells showed less resistance to select chemotherapeutics compared to the control group. Both small molecule inhibitors enhanced the outcomes of EMT-ATF silencing. Conclusion:Overall it was found that EMT-ATF silencing, either by EMT-ATF silencing or with the enhancement by small molecules, is a good candidate to treat pancreatic cancer since it simultaneously minimizes metastasis, stem cell properties, and drug resistance.

| S-EPMC7308789 | biostudies-literature

Brown recluse spider (Loxosceles reclusa) venom phospholipase D (PLD) generates lysophosphatidic acid (LPA).

Project description:Envenomation by the brown recluse spider (Loxosceles reclusa) may cause local dermonecrosis and, rarely, coagulopathies, kidney failure and death. A venom phospholipase, SMaseD (sphingomyelinase D), is responsible for the pathological manifestations of envenomation. Recently, the recombinant SMaseD from Loxosceles laeta was demonstrated to hydrolyse LPC (lysophosphatidylcholine) to produce LPA (lysophosphatidic acid) and choline. Therefore activation of LPA signalling pathways may be involved in some manifestations of Loxosceles envenomation. To begin investigating this idea, we cloned a full-length cDNA encoding L. reclusa SMaseD. The 305 amino acid sequence of the L. reclusa enzyme is 87, 85 and 60% identical with those of L. arizonica, L. intermedia and L. laeta respectively. The recombinant enzyme expressed in bacteria had broad substrate specificity. The lysophospholipids LPC, LPI (18:1-1-oleyol lysophosphatidylinositol), LPS, LPG (18:1-1-oleoyl-lysophosphatidylglycerol), LBPA (18:1-1-oleoyl-lysobisphosphatidic acid) (all with various acyl chains), lyso-platelet-activating factor (C16:0), cyclic phosphatidic acid and sphingomyelin were hydrolysed, whereas sphingosylphosphorylcholine, PC (phosphatidylcholine; C22:6, C20:4 and C6:0), oxidized PCs and PAF (platelet-activating factor; C16:0) were not hydrolysed. The PAF analogue, edelfosine, inhibited enzyme activity. Recombinant enzyme plus LPC (C18:1) induced the migration of A2058 melanoma cells, and this activity was blocked by the LPA receptor antagonist, VPC32183. The recombinant spider enzyme was haemolytic, but this activity was absent from catalytically inactive H37N (His37-->Asn) and H73N mutants. Our results demonstrate that Loxosceles phospholipase D hydrolyses a wider range of lysophospholipids than previously supposed, and thus the term 'SMaseD' is too limited in describing this enzyme.

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Searching the Human Genome for Snail and Slug With DNA@Home.

Project description:DNA@Home is a volunteer computing project that aims to use Gibbs Sampling for the identification and location of DNA control signals on full genome-scale datasets. A fault tolerant and asynchronous implementation of Gibbs sampling using the Berkeley Open Infrastructure for Network Computing (BOINC) was used to identify the location of binding sites of the SNAI1 (Snail) and SNAI2 (Slug) transcription factors across the human genome. Genes regulated by Slug but not Snail, and genes regulated by Snail but not Slug provided two datasets with known motifs. These datasets contained up to 994 DNA sequences which to our knowledge is largest scale use of Gibbs sampling for discovery of binding sites. 1000 parallel sampling walks were used to search for the presence of 1, 2 or 3 possible motifs using small, medium, and full size sets of these sequences. These runs were performed over a period of two months using over 1500 volunteered computing hosts and generated over 2.2 Terabytes of sampling data. High performance computing resources were used for post processing. This paper presents intra and inter walk analyses used to determine walk convergence. The results were validated against current biological knowledge of the Snail and Slug promoter regions and present avenues for further biological study.

| S-EPMC4794263 | biostudies-other

Reciprocal expression of Slug and Snail in human oral cancer cells.

Project description:Snail, also called Snai1, is a key regulator of EMT. Snail plays crucial roles in cancer progression, including resistance to anti-tumor drugs and invasion by various cancer cells. Slug, also known as Snai2, is also involved in the aggravation of certain tumors. In this study, we examined the roles of Slug in human oral squamous cell carcinoma (OSCC) cells. Slug is highly expressed in these cells, and Slug siRNA effectively represses anti-tumor drug resistance and invasive properties. In addition, transforming growth factor (TGF)-? upregulates the expression of Snail and Slug and promotes resistance to anti-tumor drugs in OSCC cells. Surprisingly, Slug siRNA appears to upregulate Snail expression considerably in OSCC cells. Snail siRNA also appears to upregulate Slug expression. Thus, either Slug or Snail siRNA alone partially mitigates malignant phenotypes in the presence of TGF-?, whereas both Slug and Snail siRNAs together dramatically suppress them. Therefore, Slug and Snail in tandem, but not alone, are potential therapeutic targets for nucleic acid medicines to treat oral cancer.

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