Correction to: Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and tumorigenicity in nasopharyngeal carcinoma by inhibiting cell cycle arrest.
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ABSTRACT:
SUBMITTER: Zhang J
PROVIDER: S-EPMC8672624 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:BACKGROUND:Epigenetic abnormalities play important roles in nasopharyngeal cancer (NPC), however, the epigenetic changes associated with abnormal cell proliferation remain unclear. METHODS:We detected epigenetic change of ZNF671 in NPC tissues and cell lines by bisulfite pyrosequencing. We evaluated zinc finger protein 671 (ZNF671) expression in NPC cell lines and clinical tissues using real-time PCR and western blotting. Then, we established NPC cell lines that stably overexpressed ZNF671 and knocked down ZNF671 expression to explore its function in NPC in vitro and in vivo. Additionally, we investigated the potential mechanism of ZNF671 by identifying the mitotic spindle and G2/M checkpoint pathways pathway downstream genes using gene set enrichment analysis, flow cytometry and western blotting. RESULTS:ZNF671 was hypermethylated in NPC tissues and cell lines. The mRNA and protein expression of ZNF671 was down-regulated in NPC tissues and cell lines and the mRNA expression could be upregulated after the demethylation agent 5-aza-2'-deoxycytidine treatment. Overexpression of ZNF671 suppressed NPC cell proliferation and colony formation in vitro; silencing ZNF671 using a siRNA had the opposite effects. Additionally, overexpression of ZNF671 reduced the tumorigenicity of NPC cells in xenograft model in vivo. The mechanism study determined that overexpressing ZNF671 induced S phase arrest in NPC cells by upregulating p21 and downregulating cyclin D1 and c-myc. CONCLUSIONS:Epigenetic mediated zinc finger protein 671 downregulation promotes cell proliferation and enhances tumorigenicity by inhibiting cell cycle arrest in NPC, which may represent a novel potential therapeutic target.
| S-EPMC5649082 | biostudies-literature
Project description:Induced pluripotent stem (iPS) cell technology holds vast promises for a cure to the hemoglobinopathies. Constructs and methods to safely insert therapeutic genes to correct the genetic defect need to be developed. Site-specific insertion is a very attractive method for gene therapy because the risks of insertional mutagenesis are eliminated provided that a "safe harbor" is identified, and because a single set of validated constructs can be used to correct a large variety of mutations simplifying eventual clinical use. We report here the correction of α-thalassemia major hydrops fetalis in transgene-free iPS cells using zinc finger-mediated insertion of a globin transgene in the AAVS1 site on human chromosome 19. Homozygous insertion of the best of the 4 constructs tested led to complete correction of globin chain imbalance in erythroid cells differentiated from the corrected iPS cells.
| S-EPMC3543982 | biostudies-literature
Project description:Although Krüppel-associated box domain-containing zinc-finger proteins (K-ZNFs) may be associated with sophisticated gene regulation in higher organisms, the physiological functions of most K-ZNFs remain unknown. The Zfp212 protein was highly conserved in mammals and abundant in the brain; it was mainly expressed in the cerebellum (Cb). Zfp212 (mouse homolog of human ZNF212) knockout (Zfp212-KO) mice showed a reduction in survival rate compared to wild-type mice after 20 months of age. GABAergic Purkinje cell degeneration in the Cb and aberrant locomotion were observed in adult Zfp212-KO mice. To identify genes related to the ataxia-like phenotype of Zfp212-KO mice, 39 ataxia-associated genes in the Cb were monitored. Substantial alterations in the expression of ataxin 10, protein phosphatase 2 regulatory subunit beta, protein kinase C gamma, and phospholipase D3 (Pld3) were observed. Among them, Pld3 alone was tightly regulated by Flag-tagged ZNF212 overexpression or Zfp212 knockdown in the HT22 cell line. The Cyclic Amplification and Selection of Targets assay identified the TATTTC sequence as a recognition motif of ZNF212, and these motifs occurred in both human and mouse PLD3 gene promoters. Adeno-associated virus-mediated introduction of human ZNF212 into the Cb of 3-week-old Zfp212-KO mice prevented Purkinje cell death and motor behavioral deficits. We confirmed the reduction of Zfp212 and Pld3 in the Cb of an alcohol-induced cerebellar degeneration mouse model, suggesting that the ZNF212-PLD3 relationship is important for Purkinje cell survival.
| S-EPMC8610974 | biostudies-literature
Project description:Spodoptera frugiperda SF-21 cells infected with Autographa californica nuclear polyhedrosis virus mutants which lack a functional p35 gene undergo apoptosis, a type of programmed cell death. To identify p35-homologous genes in other baculoviruses, A. californica nuclear polyhedrosis virus DNA containing a deletion in p35 was cotransfected into SF-21 cells along with genomic DNAs from other baculoviruses. One of the viral DNAs which were able to rescue wild-type infection was from Cydia pomonella granulosis virus (CpGV). The CpGV gene responsible for the effect was mapped to a 1.6-kb SalI-SstI subclone of the SalI B fragment of CpGV. The sequence of the SalI-SstI subclone revealed an open reading frame capable of encoding a polypeptide of 31 kDa which was sufficient to rescue wild-type infection; this gene was thus called iap (inhibitor of apoptosis). The predicted sequence of the IAP polypeptide exhibited no significant homology to P35 but contained a zinc finger-like motif which is also found in other genes with the potential to regulate apoptosis, including several mammalian proto-oncogenes and two insect genes involved in embryonic development. In the context of the viral genome, both iap and p35 were able to block apoptosis induced by actinomycin D, indicating that these genes act by blocking cellular apoptosis rather than by preventing viral stimulation of apoptosis. Several independent recombinant viruses derived from cotransfections with either the entire CpGV genome or the 1.6-kb subclone were characterized.
| S-EPMC240327 | biostudies-other
Project description:The radio-chemotherapy with 5-fluorouracil (5-FU) is the standard of care treatment for patients with locally advanced rectal cancer (LARC) but it is only effective for a third of them. The proteomic and transcriptomic response of three colorectal cancer (CRC) cell lines to 5-FU and radiation was assessed and correlated with their genetic background. The induction of a 5-FU-resistance in those cell lines negatively affects the levels of transcripts corresponding to Krüppel-associated box (KRAB)-containing zinc finger proteins (ZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter are down-regulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights possible new mechanisms involved in resistance to treatment and therefore potential new therapeutic targets to overcome this resistance.
2022-05-19 | PXD020000 | Pride
Project description:The radio-chemotherapy with 5-fluorouracil (5-FU) is the standard of care treatment for patients with locally advanced rectal cancer (LARC) but it is only effective for a third of them. The proteomic and transcriptomic response of three colorectal cancer (CRC) cell lines to 5-FU and radiation was assessed and correlated with their genetic background. The induction of a 5-FU-resistance in those cell lines negatively affects the levels of transcripts corresponding to Krüppel-associated box (KRAB)-containing zinc finger proteins (ZFPs), the largest family of transcriptional repressors. Among nearly 350 KRAB-ZFPs, almost a quarter are down-regulated after the induction of a 5-FU-resistance including a common one between the three CRC cell lines, ZNF649, whose role is still unknown. This proteomic, transcriptomic and genomic analysis of intrinsic and acquired resistance highlights possible new mechanisms involved in resistance to treatment and therefore potential new therapeutic targets to overcome this resistance.
2022-04-13 | GSE153412 | GEO
Project description:BackgroundIncreased levels of NF-?B are hallmarks of pancreatic ductal adenocarcinoma (PDAC) and both classical and alternative NF-?B activation pathways have been implicated.Methodology/principal findingsHere we show that activation of the alternative pathway is a source for the high basal NF-?B activity in PDAC cell lines. Increased activity of the p52/RelB NF-?B complex is mediated through stabilization and activation of NF-?B-inducing kinase (NIK). We identify proteasomal downregulation of TNF receptor-associated factor 2 (TRAF2) as a mechanism by which levels of active NIK are increased in PDAC cell lines. Such upregulation of NIK expression and activity levels relays to increased proliferation and anchorage-independent growth, but not migration or survival of PDAC cells.Conclusions/significanceRapid growth is one characteristic of pancreatic cancer. Our data indicates that the TRAF2/NIK/NF-?B2 pathway regulates PDAC cell tumorigenicity and could be a valuable target for therapy of this cancer.
| S-EPMC3536768 | biostudies-literature
Project description:The combination of induced pluripotent stem cell (iPSC) technology and targeted gene modification by homologous recombination (HR) represents a promising new approach to generate genetically corrected, patient-derived cells that could be used for autologous transplantation therapies. This strategy has several potential advantages over conventional gene therapy including eliminating the need for immunosuppression, avoiding the risk of insertional mutagenesis by therapeutic vectors, and maintaining expression of the corrected gene by endogenous control elements rather than a constitutive promoter. However, gene targeting in human pluripotent cells has remained challenging and inefficient. Recently, engineered zinc finger nucleases (ZFNs) have been shown to substantially increase HR frequencies in human iPSCs, raising the prospect of using this technology to correct disease causing mutations. Here, we describe the generation of iPSC lines from sickle cell anemia patients and in situ correction of the disease causing mutation using three ZFN pairs made by the publicly available oligomerized pool engineering method (OPEN). Gene-corrected cells retained full pluripotency and a normal karyotype following removal of reprogramming factor and drug-resistance genes. By testing various conditions, we also demonstrated that HR events in human iPSCs can occur as far as 82 bps from a ZFN-induced break. Our approach delineates a roadmap for using ZFNs made by an open-source method to achieve efficient, transgene-free correction of monogenic disease mutations in patient-derived iPSCs. Our results provide an important proof of principle that ZFNs can be used to produce gene-corrected human iPSCs that could be used for therapeutic applications.
| S-EPMC3285772 | biostudies-literature
Project description:Discovery of inhibitors for endothelial-related transcription factors can contribute to the development of anti-angiogenic therapies that treat various diseases, including cancer. The role of transcription factor Vezf1 in vascular development and regulation of angiogenesis has been defined by several earlier studies. Through construction of a computational model for Vezf1, work here has identified a novel small molecule drug capable of inhibiting Vezf1 from binding to its cognate DNA binding site. Using structure-based design and virtual screening of the NCI Diversity Compound Library, 12 shortlisted compounds were tested for their ability to interfere with the binding of Vezf1 to DNA using electrophoretic gel mobility shift assays. We identified one compound, T4, which has an IC50 of 20 ?M. Using murine endothelial cells, MSS31, we tested the effect of T4 on endothelial cell viability and angiogenesis by using tube formation assay. Our data show that addition of T4 in cell culture medium does not affect cell viability at concentrations lower or equal to its IC 50 but strongly inhibits the network formation by MSS31 in the tube formation assays. Given its potential efficacy, this inhibitor has significant therapeutic potential in several human diseases.
| S-EPMC6100598 | biostudies-literature
Project description:BackgroundBacterial infection with the severe complication of sepsis is a frequent and serious condition, being a major cause of death worldwide. To cope with the plethora of occurring bacterial infections there is therefore an urgent need to identify molecular mechanisms operating during the host response, in order both to identify potential targets for therapeutic intervention and to identify biomarkers for disease. Here we addressed this issue by studying global gene expression in uteri from female dogs suffering from spontaneously occurring uterine bacterial infection.Principal findingsThe analysis showed that almost 800 genes were significantly (p<0.05) upregulated (>2-fold) in the uteri of diseased animals. Among these were numerous chemokine and cytokine genes, as well as genes associated with inflammatory cell extravasation, anti-bacterial action, the complement system and innate immune responses, as well as proteoglycan-associated genes. There was also a striking representation of genes associated with proteolysis. Robust upregulation of immunoglobulin components and genes involved in antigen presentation was also evident, indicating elaboration of a strong adaptive immune response. The bacterial infection was also associated with a significant downregulation of almost 700 genes, of which various homeobox and zinc finger transcription factors were highly represented.Conclusions/significanceTogether, these finding outline the molecular patterns involved in bacterial infection of the uterus. The study identified altered expression of numerous genes not previously implicated in bacterial disease, and several of these may be evaluated for potential as biomarkers of disease or as therapeutic targets. Importantly, since humans and dogs show genetic similarity and develop diseases that share many characteristics, the molecular events identified here are likely to reflect the corresponding situation in humans afflicted by similar disease.
| S-EPMC2777310 | biostudies-literature