The protumor function of UHRF1 is linked to both the Akt signaling cascade and the epithelial-mesenchymal transition in esophageal cancer
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA594717 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:The epigenetic factor UHRF1 is highly expressed in many types of cancers, however, the underlying mechanism remains elusive. Here we report an oncogenic function of UHRF1 in esophageal cancer(EC). UHRF1 was observed to be robustly expressed in EC cells. Knockdown of UHRF1 was achieved in two EC cell lines TE-10 and Kyse410 using a shRNA-mediated lentivirus system. Silencing of UHRF1 led to the inhibition of the proliferation and the mesenchymal phenotype as determined by the wound-healing and the invasion-in-matrigel assays. Transcriptome profile analysis revealed that two groups of the genes are significantly suppressed upon the UHRF1-shRNA expression. One group is linked to Akt signal pathway and the other is linked to the epithelial-mesenchymal transition. MK2206, an Akt inhibitor, could also inhibit the growth and the mesenchymal phenotype of EC cells. But interestingly, while UHRF1 deficiency resulted in the downregulation of EMT-associated genes such as ZEB2, vimentin and twist1, MK2206 inhibition of Akt activity only suppressed the expression of snail, suggesting that the control of the mesenchymal phenotype by UHRF1 does not rely on the AKT cascade. We conclude that the oncogenic function of UHRF1 is linked to the synergistic effect on the Akt signal cascade and the EMT-specific genes in EC cells.
2022-12-10 | GSE141781 | GEO
Project description:Deletion of Uhrf1 resulted in stage 1-specific defects during iNKT cell development. To investigate the molecular mechanism, we sorted WT and Uhrf1-KO stage 1 iNKT cells and performed RNA-seq. By comparing gene expression profile, we found metabolic defects in Uhrf1-KO stage 1 iNKT cells. The expression of CD71 (Tfrc), two subunits of CD98 (Slc3a2 and Slc7a5) and Glut3 (Slc2a3) was reduced in stage 1 iNKT cells. Besides, the downstream pathways of AKT-mTOR axis were significantly reduced. Collectively, our results suggest that Uhrf1 is required for iNKT cell development by regulating the Akt-mTOR signaling pathway. We first sorted WT and Uhrf1-KO stage 1 iNKT cells, extracted the mRNA and performed RNA-seq. We then analyzed the differentially expressed genes and performed KEGG pathway analysis. We used RT-PCR to verify the expression of the key nutrient related genes (Tfrc, Slc3a2, Slc7a5 and Slc2a3) and used flow cytometry to test the protein level of metabolic related molecules. Besides, we also analyzed the expression of genes of mTOR downstream pathways to demonstrate that Uhrf1 mediated AKt-mTOR axis regulates iNKT cell development.
2016-03-10 | E-GEOD-77941 | biostudies-arrayexpress
Project description:Deletion of Uhrf1 resulted in stage 1-specific defects during iNKT cell development. To investigate the molecular mechanism, we sorted WT and Uhrf1-KO stage 1 iNKT cells and performed RNA-seq. By comparing gene expression profile, we found metabolic defects in Uhrf1-KO stage 1 iNKT cells. The expression of CD71 (Tfrc), two subunits of CD98 (Slc3a2 and Slc7a5) and Glut3 (Slc2a3) was reduced in stage 1 iNKT cells. Besides, the downstream pathways of AKT-mTOR axis were significantly reduced. Collectively, our results suggest that Uhrf1 is required for iNKT cell development by regulating the Akt-mTOR signaling pathway.
2016-03-10 | GSE77941 | GEO
Project description:UHRF1 (Ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 to hemimethylated DNA during replication, is essential for maintaining DNA methylation patterns during cell division and is suggested to direct additional repressive epigenetic marks. Uhrf1 mutation in zebrafish results in multiple embryonic defects including failed hepatic outgrowth, but the epigenetic basis of these phenotypes is not known. We find that DNA methylation is the only epigenetic mark that is depleted in uhrf1 mutants and make the surprising finding that despite the reduced organ size in uhrf1 mutants, genes regulating DNA replication and S-phase progression were highly upregulated. Further, there is a striking increase in BrdU incorporation in uhrf1 mutant cells, and they retained BrdU labeling over several days, indicating they are arrested in S-phase. Moreover, some of the label retaining nuclei co-localized with TUNEL positive nuclei, suggesting that arrested cells are responsible for apoptosis. Importantly, dnmt1 mutation phenocopies the S-phase arrest and hepatic outgrowth defects in uhrf1 mutants and Dnmt1 knock-down enhances the uhrf1 hepatic phenotype. Together, these data indicate that DNA hypomethylation is sufficient to generate the uhrf1 mutant phenotype by promoting an S-phase arrest. We thus propose that cell cycle arrest is a mechanism to restrict propagation of epigenetically deranged cells during embryogenesis. Genome-wide expression profiling was performed on 2 uhrf1 mutant and 2 wildtype zebrafish larvae (120 hours post fertilization) by using Zebrafish Genome Array (Affymetrix) according to manufacturer's instruction.
2015-02-09 | E-GEOD-55339 | biostudies-arrayexpress
Project description:We used microarrays to explore the expression profile from cells expressing wild type and UHRF1 S674A mutant. HeLa cells expressing UHRF1 WT and S674A mutant showed similar gene expression pattern without significant affecting the transcription of DNA repari genes. UHRF1 was depleted in HeLa cells by shRNA treatment. Total RNA was purified and used to determine the global gene transcription profiles by microarray assays. The UHRF1-related genes expression profiles were compared among control cells, UHRF1-depleted cells, UHRF1 WT reconstituting cells and UHRF1 S674A mutant reconstituting cells.
2016-01-05 | E-GEOD-73751 | biostudies-arrayexpress
Project description:Cholangiocarcinoma (CCA) is a highly malignant tumor characterized by a lack of effective targeted therapeutic strategies. The protein UHRF1 plays a pivotal role in the preservation of DNA methylation and works synergistically with DNMT1. Posttranscriptional modifications (PTMs), such as ubiquitination, play indispensable roles in facilitating this process. Nevertheless, the specific PTMs that regulate UHRF1 in CCA remain unidentified. We confirmed the interaction between STUB1 and UHRF1 through mass spectrometry analysis. Furthermore, we investigated the underlying mechanisms of the STUB1-UHRF1/DNMT1 axis via co-IP experiments, denaturing IP ubiquitination experiments, nuclear‒cytoplasmic separation and immunofluorescence experiments. STUB1-UHRF1/DNMT1-mediated DNA methylation plays a crucial role in promoting the epigenetic silencing of tumor suppressor genes (TSGs) and facilitating tumor progression. To investigate the specific TSGs regulated by the STUB1-UHRF1/DNMT1 axis in CCA cells, RNA-seq analysis of overexpressed STUB1 and negative control TFK1 cells was performed.
2024-09-16 | GSE275480 | GEO
Project description:Omipalisib Inhibits Esophageal Cancer Growth through PI3K/AKT/mTOR Signalling Pathway Disruption
| PRJNA600533 | ENA
Project description:CEBPG promotes esophageal squamous cell carcinoma progression by enhancing PI3K-AKT signaling
| PRJNA657203 | ENA
Project description:Histone methylation occurs on both lysine and arginine residues and its dynamic regulation plays a critical role in chromatin biology. Here we identify the UHRF1 PHD domain (PHDUHRF1), an important regulator of DNA CpG methylation, as an unanticipated histone H3 unmodified arginine 2 (H3R2)-recognition modality. This conclusion is based on binding studies and co-crystal structures of the PHDUHRF1 bound to histone H3 peptides, where the guanidinium group of unmodified R2 forms an extensive intermolecular hydrogen bond network, with methylation of H3R2, but not H3K4 or H3K9, disrupting complex formation. We have identified direct target genes of UHRF1 from microarray and ChIP studies. Importantly, we show that UHRF1’s ability to repress its direct target gene expression is dependent on PHDUHRF1 binding to unmodified H3R2, thereby demonstrating the functional importance of this recognition event and supporting the potential for crosstalk between histone arginine methylation and UHRF1 function. UHRF1 protein was depleted in HCT116 cells by shRNA treatment. Total RNA was purified and used to determine the global gene transcription profiles by microarray assays. The UHRF1-regulated genes were identified by comparing the gene expression profiles of control and UHRF1-depleted HCT116 cells.
2011-07-07 | E-GEOD-30478 | biostudies-arrayexpress
Project description:The multi-domain protein UHRF1 (ubiquitin-like, containing PHD and RING finger domains, 1) recruits DNMT1 for DNA methylation maintenance during DNA replication. Here, we show that MOF (Males absent On the First) is an acetyltransferase of UHRF1 to acetylate UHRF1 at Lys670 in the pre-RING linker region whereas HDAC1 is a deacetylase of UHRF1 at the same site. The MOF/HDAC1-mediated acetylation in UHRF1 is cell-cycle regulated and peaks at G1/S phase, in line with the function of UHRF1 in recruiting DNMT1 to maintain DNA methylation. In addition, UHRF1 acetylation significantly enhances its E3 ligase activity and elimination of UHRF1 acetylation at these sites attenuates UHRF1-mediated H3 ubiquitination, which in turn impairs the DNMT1 recruitment and DNA methylation. Taken together, these findings not only identify MOF as a new acetyltransferase for UHRF1 but also reveal a novel mechanism underlying the regulation of DNA methylation maintenance through MOF-mediated UHRF1 acetylation.
2024-03-06 | PXD040426 | Pride