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2.
Br J Cancer ; 129(12): 1903-1914, 2023 12.
Article in English | MEDLINE | ID: mdl-37875732

ABSTRACT

BACKGROUND: Neuroendocrine prostate cancer (NEPC) is an aggressive form of prostate cancer, arising from resistance to androgen-deprivation therapies. However, the molecular mechanisms associated with NEPC development and invasiveness are still poorly understood. Here we investigated the expression and functional significance of Fascin-1 (FSCN1), a pro-metastasis actin-bundling protein associated with poor prognosis of several cancers, in neuroendocrine differentiation of prostate cancer. METHODS: Differential expression analyses using Genome Expression Omnibus (GEO) database, clinical samples and cell lines were performed. Androgen or antagonist's cellular treatments and knockdown experiments were used to detect changes in cell morphology, molecular markers, migration properties and in vivo tumour growth. Chromatin immunoprecipitation-sequencing (ChIP-Seq) data and ChIP assays were analysed to decipher androgen receptor (AR) binding. RESULTS: We demonstrated that FSCN1 is upregulated during neuroendocrine differentiation of prostate cancer in vitro, leading to phenotypic changes and NEPC marker expression. In human prostate cancer samples, FSCN1 expression is restricted to NEPC tumours. We showed that the androgen-activated AR downregulates FSCN1 expression and works as a transcriptional repressor to directly suppress FSCN1 expression. AR antagonists alleviate this repression. In addition, FSCN1 silencing further impairs in vivo tumour growth. CONCLUSION: Collectively, our findings identify FSCN1 as an AR-repressed gene. Particularly, it is involved in NEPC aggressiveness. Our results provide the rationale for the future clinical development of FSCN1 inhibitors in NEPC patients.


Subject(s)
Prostatic Neoplasms , Receptors, Androgen , Humans , Male , Androgen Antagonists/therapeutic use , Androgens , Cell Line, Tumor , Gene Expression Regulation, Neoplastic , Microfilament Proteins/genetics , Microfilament Proteins/metabolism , Prostatic Neoplasms/genetics , Prostatic Neoplasms/pathology , Receptors, Androgen/genetics , Receptors, Androgen/metabolism , Neuroendocrine Tumors/genetics , Neuroendocrine Tumors/pathology
3.
Eur Urol ; 79(2): 200-211, 2021 02.
Article in English | MEDLINE | ID: mdl-33176972

ABSTRACT

BACKGROUND: Deleterious ATM alterations are found in metastatic prostate cancer (PC); PARP inhibition has antitumour activity against this subset, but only some ATM loss PCs respond. OBJECTIVE: To characterise ATM-deficient lethal PC and to study synthetic lethal therapeutic strategies for this subset. DESIGN, SETTING, AND PARTICIPANTS: We studied advanced PC biopsies using validated immunohistochemical (IHC) and next-generation sequencing (NGS) assays. In vitro cell line models modified using CRISPR-Cas9 to impair ATM function were generated and used in drug-sensitivity and functional assays, with validation in a patient-derived model. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: ATM expression by IHC was correlated with clinical outcome using Kaplan-Meier curves and log-rank test; sensitivity to different drug combinations was assessed in the preclinical models. RESULTS AND LIMITATIONS: Overall, we detected ATM IHC loss in 68/631 (11%) PC patients in at least one biopsy, with synchronous and metachronous intrapatient heterogeneity; 46/71 (65%) biopsies with ATM loss had ATM mutations or deletions by NGS. ATM IHC loss was not associated with worse outcome from advanced disease, but ATM loss was associated with increased genomic instability (NtAI:number of subchromosomal regions with allelic imbalance extending to the telomere, p = 0.005; large-scale transitions, p = 0.05). In vitro, ATM loss PC models were sensitive to ATR inhibition, but had variable sensitivity to PARP inhibition; superior antitumour activity was seen with combined PARP and ATR inhibition in these models. CONCLUSIONS: ATM loss in PC is not always detected by targeted NGS, associates with genomic instability, and is most sensitive to combined ATR and PARP inhibition. PATIENT SUMMARY: Of aggressive prostate cancers, 10% lose the DNA repair gene ATM; this loss may identify a distinct prostate cancer subtype that is most sensitive to the combination of oral drugs targeting PARP and ATR.


Subject(s)
Ataxia Telangiectasia Mutated Proteins/antagonists & inhibitors , Ataxia Telangiectasia Mutated Proteins/genetics , Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use , Prostatic Neoplasms/drug therapy , Prostatic Neoplasms/genetics , Humans , Male , Neoplasm Staging , Prostatic Neoplasms/pathology , Retrospective Studies , Tumor Cells, Cultured
4.
Aging Cell ; 19(4): e13133, 2020 04.
Article in English | MEDLINE | ID: mdl-32175667

ABSTRACT

Senescence is a stable growth arrest that impairs the replication of damaged, old or preneoplastic cells, therefore contributing to tissue homeostasis. Senescent cells accumulate during ageing and are associated with cancer, fibrosis and many age-related pathologies. Recent evidence suggests that the selective elimination of senescent cells can be effective on the treatment of many of these senescence-associated diseases. A universal characteristic of senescent cells is that they display elevated activity of the lysosomal ß-galactosidase, and this has been exploited as a marker for senescence (senescence-associated ß-galactosidase activity). Consequently, we hypothesized that galactose-modified cytotoxic prodrugs will be preferentially processed by senescent cells, resulting in their selective killing. Here, we show that different galactose-modified duocarmycin (GMD) derivatives preferentially kill senescent cells. GMD prodrugs induce selective apoptosis of senescent cells in a lysosomal ß-galactosidase (GLB1)-dependent manner. GMD prodrugs can eliminate a broad range of senescent cells in culture, and treatment with a GMD prodrug enhances the elimination of bystander senescent cells that accumulate upon whole-body irradiation treatment of mice. Moreover, taking advantage of a mouse model of adamantinomatous craniopharyngioma (ACP), we show that treatment with a GMD prodrug selectively reduced the number of ß-catenin-positive preneoplastic senescent cells. In summary, the above results make a case for testing the potential of galactose-modified duocarmycin prodrugs to treat senescence-related pathologies.


Subject(s)
Antibiotics, Antineoplastic/pharmacology , Cellular Senescence/drug effects , Craniopharyngioma/drug therapy , Duocarmycins/pharmacology , Galactose/pharmacology , Prodrugs/pharmacology , Animals , Apoptosis/drug effects , Cell Line , Coculture Techniques , Craniopharyngioma/metabolism , Craniopharyngioma/pathology , Humans , Mice , Mice, Inbred C57BL , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/metabolism , Neoplasms, Experimental/pathology , beta-Galactosidase/metabolism
5.
Nat Metab ; 1(11): 1074-1088, 2019 11.
Article in English | MEDLINE | ID: mdl-31799499

ABSTRACT

Senescence is a cellular stress response that results in the stable arrest of old, damaged or preneoplastic cells. Oncogene-induced senescence is tumor suppressive but can also exacerbate tumorigenesis through the secretion of pro-inflammatory factors from senescent cells. Drugs that selectively kill senescent cells, termed senolytics, have proved beneficial in animal models of many age-associated diseases. Here, we show that the cardiac glycoside, ouabain, is a senolytic agent with broad activity. Senescent cells are sensitized to ouabain-induced apoptosis, a process mediated in part by induction of the pro-apoptotic Bcl2-family protein NOXA. We show that cardiac glycosides synergize with anti-cancer drugs to kill tumor cells and eliminate senescent cells that accumulate after irradiation or in old mice. Ouabain also eliminates senescent preneoplastic cells. Our findings suggest that cardiac glycosides may be effective anti-cancer drugs by acting through multiple mechanism. Given the broad range of senescent cells targeted by cardiac glycosides their use against age-related diseases warrants further exploration.


Subject(s)
Cardiac Glycosides/pharmacology , Cellular Senescence/drug effects , Animals , Antineoplastic Agents/pharmacology , Apoptosis/drug effects , Humans , Mice , Ouabain/pharmacology , Quercetin/pharmacology , Rats
6.
Cancer Cell ; 34(1): 85-102.e9, 2018 07 09.
Article in English | MEDLINE | ID: mdl-29990503

ABSTRACT

Oncogene-induced senescence is a potent tumor-suppressive response. Paradoxically, senescence also induces an inflammatory secretome that promotes carcinogenesis and age-related pathologies. Consequently, the senescence-associated secretory phenotype (SASP) is a potential therapeutic target. Here, we describe an RNAi screen for SASP regulators. We identified 50 druggable targets whose knockdown suppresses the inflammatory secretome and differentially affects other SASP components. Among the screen candidates was PTBP1. PTBP1 regulates the alternative splicing of genes involved in intracellular trafficking, such as EXOC7, to control the SASP. Inhibition of PTBP1 prevents the pro-tumorigenic effects of the SASP and impairs immune surveillance without increasing the risk of tumorigenesis. In conclusion, our study identifies SASP inhibition as a powerful and safe therapy against inflammation-driven cancer.


Subject(s)
Cell Transformation, Neoplastic/metabolism , Cellular Senescence , Heterogeneous-Nuclear Ribonucleoproteins/metabolism , Inflammation/metabolism , Neoplasms/metabolism , Polypyrimidine Tract-Binding Protein/metabolism , Alternative Splicing , Animals , Cell Proliferation , Cell Transformation, Neoplastic/genetics , Cell Transformation, Neoplastic/pathology , Female , Gene Expression Regulation, Neoplastic , Heterogeneous-Nuclear Ribonucleoproteins/genetics , Humans , Inflammation/genetics , Inflammation/pathology , Inflammation/therapy , MCF-7 Cells , Mice, Inbred C57BL , Mice, Transgenic , Neoplasms/genetics , Neoplasms/pathology , Neoplasms/prevention & control , Paracrine Communication , Phenotype , Polypyrimidine Tract-Binding Protein/genetics , RNA Interference , Signal Transduction , Tumor Burden , Vesicular Transport Proteins/genetics , Vesicular Transport Proteins/metabolism
7.
J Clin Invest ; 128(4): 1238-1246, 2018 04 02.
Article in English | MEDLINE | ID: mdl-29608137

ABSTRACT

Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation. In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non-cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored. In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit.


Subject(s)
Aging , Autophagy , Cellular Senescence , Neoplasms , Aging/metabolism , Aging/pathology , Animals , Humans , Neoplasms/metabolism , Neoplasms/pathology , Neoplasms/physiopathology , Neoplasms/therapy
8.
Aging (Albany NY) ; 9(1): 114-132, 2016 12 15.
Article in English | MEDLINE | ID: mdl-27992856

ABSTRACT

Cancer-associated fibroblasts (CAF) remain a poorly characterized, heterogeneous cell population. Here we characterized two previously described tumor-promoting CAF sub-types, smooth muscle actin (SMA)-positive myofibroblasts and senescent fibroblasts, identifying a novel link between the two. Analysis of CAF cultured ex vivo, showed that senescent CAF are predominantly SMA-positive; this was confirmed by immunochemistry in head & neck (HNSCC) and esophageal (EAC) cancers. In vitro, we found that fibroblasts induced to senesce develop molecular, ultrastructural and contractile features typical of myofibroblasts and this is dependent on canonical TGF-ß signaling. Similar to TGF-ß1-generated myofibroblasts, these cells secrete soluble factors that promote tumor cell motility. However, RNA-sequencing revealed significant transcriptomic differences between the two SMA-positive CAF groups, particularly in genes associated with extracellular matrix (ECM) deposition and organization, which differentially promote tumor cell invasion. Notably, second harmonic generation imaging and bioinformatic analysis of SMA-positive human HNSCC and EAC showed that collagen fiber organization correlates with poor prognosis, indicating that heterogeneity within the SMA-positive CAF population differentially impacts on survival. These results show that non-fibrogenic, SMA-positive myofibroblasts can be directly generated through induction of fibroblast senescence and suggest that senescence and myofibroblast differentiation are closely linked processes.


Subject(s)
Cell Differentiation/physiology , Cellular Senescence/physiology , Fibroblasts/pathology , Myofibroblasts/pathology , Neoplasms/pathology , Animals , Cell Line, Tumor , Extracellular Matrix/metabolism , Fibroblasts/metabolism , Humans , Mice , Myofibroblasts/metabolism , Neoplasms/metabolism , Phenotype , Prognosis , Signal Transduction/physiology , Transforming Growth Factor beta1/metabolism
9.
FEBS J ; 283(23): 4263-4273, 2016 12.
Article in English | MEDLINE | ID: mdl-27735137

ABSTRACT

Methylation of histone H3 lysine 4 is linked to active transcription and can be removed by LSD1 or the JmjC domain-containing proteins by amino-oxidation or hydroxylation, respectively. Here we describe that its deamination can be catalyzed by lysyl oxidase-like 2 protein (LOXL2), presenting an unconventional chemical mechanism for H3K4 modification. Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4. Moreover, by regulating H3K4me3 deamination, LOXL2 activity is linked with the transcriptional control of the CDH1 gene. These results reveal the existence of further H3 modification as well as a novel mechanism for H3K4me3 demethylation. DATABASE: The GEO accession number for the data referred to this paper is GSE35600.


Subject(s)
Amino Acid Oxidoreductases/metabolism , Histones/metabolism , Lysine/metabolism , Amino Acid Oxidoreductases/genetics , Antigens, CD , Blotting, Western , Cadherins/genetics , Cadherins/metabolism , Cell Line , Cell Line, Tumor , Gene Expression Profiling , Gene Expression Regulation , Humans , Methylation , Oxidation-Reduction , RNA Interference , Reverse Transcriptase Polymerase Chain Reaction , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Spectrophotometry, Infrared
11.
EMBO J ; 35(7): 701-2, 2016 Apr 01.
Article in English | MEDLINE | ID: mdl-26905295

ABSTRACT

Mitochondrial dysfunction has been linked to both cellular senescence and ageing. Despite the relationship, it is still unclear whether mitochondria have a causal role in senescence. In this issue of The EMBO Journal, Correia-Melo et al (2016) combine targeted depletion of mitochondria with impairment of their biogenesis to demonstrate that decreased numbers of mitochondria impair the senescence response. Their results suggest that targeting mitochondria could reduce the detrimental effects of senescence during ageing.


Subject(s)
Aging/physiology , Mitochondria/physiology , Animals , Humans
14.
Nat Cell Biol ; 17(9): 1205-17, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26280535

ABSTRACT

Senescent cells secrete a combination of factors collectively known as the senescence-associated secretory phenotype (SASP). The SASP reinforces senescence and activates an immune surveillance response, but it can also show pro-tumorigenic properties and contribute to age-related pathologies. In a drug screen to find new SASP regulators, we uncovered the mTOR inhibitor rapamycin as a potent SASP suppressor. Here we report a mechanism by which mTOR controls the SASP by differentially regulating the translation of the MK2 (also known as MAPKAPK2) kinase through 4EBP1. In turn, MAPKAPK2 phosphorylates the RNA-binding protein ZFP36L1 during senescence, inhibiting its ability to degrade the transcripts of numerous SASP components. Consequently, mTOR inhibition or constitutive activation of ZFP36L1 impairs the non-cell-autonomous effects of senescent cells in both tumour-suppressive and tumour-promoting contexts. Altogether, our results place regulation of the SASP as a key mechanism by which mTOR could influence cancer, age-related diseases and immune responses.


Subject(s)
Intracellular Signaling Peptides and Proteins/metabolism , Phosphoproteins/metabolism , Protein Biosynthesis , Protein Serine-Threonine Kinases/metabolism , Proteome/metabolism , TOR Serine-Threonine Kinases/physiology , Animals , Cell Line, Tumor , Cellular Senescence , Female , HEK293 Cells , Humans , Intracellular Signaling Peptides and Proteins/genetics , Mice, Nude , Neoplasm Transplantation , Protein Serine-Threonine Kinases/genetics
15.
Mol Cell ; 52(5): 746-57, 2013 Dec 12.
Article in English | MEDLINE | ID: mdl-24239292

ABSTRACT

Although heterochromatin is enriched with repressive traits, it is also actively transcribed, giving rise to large amounts of noncoding RNAs. Although these RNAs are responsible for the formation and maintenance of heterochromatin, little is known about how their transcription is regulated. Here, we show that the Snail1 transcription factor represses mouse pericentromeric transcription, acting through the H3K4 deaminase LOXL2. Since Snail1 plays a key role in the epithelial-to-mesenchymal transition (EMT), we analyzed the regulation of heterochromatin transcription in this process. At the onset of EMT, one of the major structural heterochromatin proteins, HP1α, is transiently released from heterochromatin foci in a Snail1/LOXL2-dependent manner, concomitantly with a downregulation of major satellite transcription. Moreover, preventing the downregulation of major satellite transcripts compromised the migratory and invasive behavior of mesenchymal cells. We propose that Snail1 regulates heterochromatin transcription through LOXL2, thus creating the favorable transcriptional state necessary for completing EMT.


Subject(s)
Amino Acid Oxidoreductases/genetics , Epithelial-Mesenchymal Transition/genetics , Heterochromatin/genetics , Transcription Factors/genetics , Transcription, Genetic , Animals , Cell Line , Chromobox Protein Homolog 5 , Chromosomal Proteins, Non-Histone/genetics , Down-Regulation , HEK293 Cells , Histones/genetics , Humans , Mesoderm/metabolism , Mice , Snail Family Transcription Factors
16.
Mol Cell ; 46(3): 369-76, 2012 05 11.
Article in English | MEDLINE | ID: mdl-22483618

ABSTRACT

Methylation of lysine 4 (K4) within histone H3 has been linked to active transcription and is removed by LSD1 and the JmjC domain-containing proteins by amino-oxidation or hydroxylation, respectively. Here, we describe the deamination catalyzed by Lysyl oxidase-like 2 protein (LOXL2) as an unconventional chemical mechanism for H3K4 modification. Infrared spectroscopy and mass spectrometry analyses demonstrated that recombinant LOXL2 specifically deaminates trimethylated H3K4. Moreover, LOXL2 activity is linked with the transcriptional control of CDH1 gene by regulating H3K4me3 deamination. These results reveal another H3 modification and provide a different mechanism for H3K4 modification.


Subject(s)
Amino Acid Oxidoreductases/physiology , Histones/metabolism , Antigens, CD , Cadherins/genetics , Cell Line, Tumor , Deamination , Gene Expression Regulation , Humans , Lysine/metabolism , Methylation
17.
Mol Cell Biol ; 28(15): 4772-81, 2008 Aug.
Article in English | MEDLINE | ID: mdl-18519590

ABSTRACT

The transcriptional factor Snail1 is a repressor of E-cadherin (CDH1) gene expression essential for triggering epithelial-mesenchymal transition. Snail1 represses CDH1, directly binding its promoter and inducing the synthesis of the Zeb1 repressor. In this article, we show that repression of CDH1 by Snail1, but not by Zeb1, is dependent on the activity of Polycomb repressive complex 2 (PRC2). Embryonic stem (ES) cells null for Suz12, one of the components of PRC2, show higher levels of Cdh1 mRNA than control ES cells. In tumor cells, interference of PRC2 activity prevents the ability of Snail1 to downregulate CDH1 and partially derepresses CDH1. Chromatin immunoprecipitation assays demonstrated that Snail1 increases the binding of Suz12 to the CDH1 promoter and the trimethylation of lysine 27 in histone H3. Moreover, Snail1 interacts with Suz12 and Ezh2, as shown by coimmunoprecipitation experiments. In conclusion, these results demonstrate that Snail1 recruits PRC2 to the CDH1 promoter and requires the activity of this complex to repress E-cadherin expression.


Subject(s)
Cadherins/metabolism , Repressor Proteins/metabolism , Transcription Factors/metabolism , Animals , Binding Sites , Cadherins/genetics , Cell Line , Cell Line, Tumor , Down-Regulation , Embryo, Mammalian/cytology , Embryo, Mammalian/metabolism , Embryonic Stem Cells/cytology , Embryonic Stem Cells/metabolism , Gene Expression Regulation, Neoplastic , Humans , Mesoderm/cytology , Mesoderm/metabolism , Mice , Polycomb Repressive Complex 2 , Polycomb-Group Proteins , Promoter Regions, Genetic/genetics , Protein Binding , Protein Structure, Tertiary , RNA, Messenger/genetics , RNA, Messenger/metabolism , Snail Family Transcription Factors , Transcription Factors/chemistry
18.
Mol Cell Biol ; 28(5): 1528-40, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18172008

ABSTRACT

The product of the Snail1 gene is a transcriptional repressor required for triggering the epithelial-to-mesenchymal transition. Furthermore, ectopic expression of Snail1 in epithelial cells promotes resistance to apoptosis. In this study, we demonstrate that this resistance to gamma radiation-induced apoptosis caused by Snail1 is associated with the inhibition of PTEN phosphatase. In MDCK cells, mRNA levels of the p53 target gene PTEN are induced after gamma radiation; the transfection of Snail1 prevents this up-regulation. Decreased mRNA levels of PTEN were also detected in RWP-1 cells after the ectopic expression of this transcriptional factor. Snail1 represses and associates to the PTEN promoter as detected both by the electrophoretic mobility shift assay and chromatin immunoprecipitation experiments performed with either endogenous or ectopic Snail1. The binding of Snail1 to the PTEN promoter increases after gamma radiation, correlating with the stabilization of Snail1 protein, and prevents the association of p53 to the PTEN promoter. These results stress the critical role of Snail1 in the control of apoptosis and demonstrate the regulation of PTEN phosphatase by this transcriptional repressor.


Subject(s)
Apoptosis/radiation effects , Gamma Rays , Gene Expression Regulation , PTEN Phosphohydrolase/antagonists & inhibitors , Transcription Factors/metabolism , Animals , Cell Line , Cell Line, Tumor , Chromatin Immunoprecipitation , DNA Damage , DNA, Complementary , Dogs , G2 Phase , Genes, Reporter , Humans , Luciferases, Firefly/analysis , Luciferases, Firefly/metabolism , Luciferases, Renilla/analysis , Luciferases, Renilla/metabolism , Luminescent Agents/metabolism , Pancreatic Neoplasms/pathology , Promoter Regions, Genetic , Protein Synthesis Inhibitors/pharmacology , Proto-Oncogene Proteins c-akt/metabolism , Puromycin/pharmacology , RNA, Messenger/metabolism , RNA, Small Interfering/pharmacology , Selection, Genetic , Snail Family Transcription Factors , Time Factors , Transcription Factors/genetics , Transcription Factors/pharmacology , Transfection
19.
Nucleic Acids Res ; 34(7): 2077-84, 2006.
Article in English | MEDLINE | ID: mdl-16617148

ABSTRACT

The product of Snail1 gene is a transcriptional repressor of E-cadherin expression and an inductor of the epithelial-mesenchymal transition in several epithelial tumour cell lines. Transcription of Snail1 is induced when epithelial cells are forced to acquire a mesenchymal phenotype. In this work we demonstrate that Snail1 protein limits its own expression: Snail1 binds to an E-box present in its promoter (at -146 with respect to the transcription start) and represses its activity. Therefore, mutation of the E-box increases Snail1 transcription in epithelial and mesenchymal cells. Evidence of binding of ectopic or endogenous Snail1 to its own promoter was obtained by chromatin immunoprecipitation (ChIP) experiments. Studies performed expressing different forms of Snail1 under the control of its own promoter demonstrate that disruption of the regulatory loop increases the cellular levels of Snail protein. These results indicate that expression of Snail1 gene can be regulated by its product and evidence the existence of a fine-tuning feed-back mechanism of regulation of Snail1 transcription.


Subject(s)
E-Box Elements , Gene Expression Regulation , Promoter Regions, Genetic , Repressor Proteins/genetics , Transcription Factors/genetics , Animals , Binding Sites , Cell Line , Down-Regulation , Homeostasis , Humans , Mice , RNA, Messenger/metabolism , Repressor Proteins/metabolism , Snail Family Transcription Factors , Transcription Factors/metabolism
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