Cytoplasmic UHRF1 restrains MHC-I-mediated anti-tumor immune response
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1085386 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Immunotherapy has revolutionized the landscape of cancer treatment. However, both primary and acquired resistance to immunotherapy, emerged during the co-evolution of cancer cells and the tumor microenvironment (TME), commonly restrain long-term tumor control. In exploring the oncogenic activity of Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), we unexpectedly discovered that this epigenetic regulator exhibits altered expression and aberrant cytosolic localization in cancerous tissues. Cytoplasmic translocation of UHRF1 is induced by its phosphorylation on a specific serine in response to signals provided by factors present in the TME, such as TGF-, enabling UHRF1 to bind MHC-I and promote its ubiquitination and degradation via the E3 activity of UHRF1. Down-regulation of MHC-I results in suppression of the antigen presentation pathway to establish a non-T cell-inflamed TME favoring tumor growth. Genetic deletion of UHRF1 synergizes with immune checkpoint blockade (ICB) treatment and induces an anti-tumor memory response by evoking low-affinity T cells upon sustained UHRF1 inactivation. Our study unveils a novel function of UHRF1 in cancer immune evasion and provides a potential target to synergize with immunotherapy and overcome immunotherapeutic resistance.
2024-08-09 | GSE261146 | GEO
Project description:Cytoplasmic UHRF1 restrains MHC-I-mediated anti-tumor immune response [bulk RNA-seq]
| PRJNA1139165 | ENA
Project description:Immunotherapy has revolutionized the landscape of cancer treatment. However, both primary and acquired resistance to immunotherapy, emerged during the co-evolution of cancer cells and the tumor microenvironment (TME), commonly restrain long-term tumor control. In exploring the oncogenic activity of Ubiquitin-like with PHD and ring finger domains 1 (UHRF1), we unexpectedly discovered that this epigenetic regulator exhibits altered expression and aberrant cytosolic localization in cancerous tissues. Cytoplasmic translocation of UHRF1 is induced by its phosphorylation on a specific serine in response to signals provided by factors present in the TME, such as TGF-, enabling UHRF1 to bind MHC-I and promote its ubiquitination and degradation via the E3 activity of UHRF1. Down-regulation of MHC-I results in suppression of the antigen presentation pathway to establish a non-T cell-inflamed TME favoring tumor growth. Genetic deletion of UHRF1 synergizes with immune checkpoint blockade (ICB) treatment and induces an anti-tumor memory response by evoking low-affinity T cells upon sustained UHRF1 inactivation. Our study unveils a novel function of UHRF1 in cancer immune evasion and provides a potential target to synergize with immunotherapy and overcome immunotherapeutic resistance.
2024-08-09 | GSE272880 | 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:TIM-3 restrains anti-tumour immunity by regulating inflammasome activation.
| PRJNA637635 | ENA
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: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:Immune checkpoint blockade (ICB) therapy revolutionized cancer treatment, but many patients with impaired MHC-I expression remain refractory. Histone methylation was involved in anti-tumor immunity of ICB. However, the link between histone methylation and MHC-I regulation and the related mechanisms are poorly understood. Here we show that KDM5A, an H3K4 demethylase that is critical for MHC-I expression and associated antigen presentation capacity, induces robust immune response and enhances ICB efficacy. Mechanistically, KDM5A upregulates IFN-gamma/STAT1-mediated MHC-I expression via directly binding and suppressing Scos1 in tumor cells. The genes encoding the lysosomal cathepsins are recognized and up-regulated by KDM5A, resulting in enhanced antigen-presentation abilities of both tumor cells and dendritic cells. Furthermore, pharmacological enhancing KDM5A improves response to anti-PD-1 therapy. These investigations demonstrate that enhancing KDM5A triggers MHC-associated antigen presentation of both tumor cells and DCs simultaneously to boost antitumor immunity, thus represents a candidate ICB sensitizer.
2024-03-31 | GSE260912 | GEO
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:There is increasing recognition of the prognostic significance of tumor cell major histocompatibility complex (MHC) class II expression in anti-cancer immunity. Relapse of acute myeloid leukemia (AML) following allogeneic stem cell transplantation (alloSCT) has recently been linked to MHC class II silencing in leukemic blasts; however, the regulation of MHC class II expression remains incompletely understood. Utilizing unbiased CRISPR-Cas9 screens, we identify that the C-terminal binding protein (CtBP) complex transcriptionally represses MHC class II pathway genes, while the E3 ubiquitin ligase complex component FBXO11 mediates degradation of CIITA, the principal transcription factor regulating MHC class II expression. Targeting these repressive mechanisms selectively induces MHC class II upregulation across a range of AML cell lines. Functionally, MHC class II+ leukemic blasts stimulate antigen-dependent CD4+ T cell activation and potent anti-tumor immune responses, providing fundamental insights into the graft-versus-leukemia effect. These findings establish the rationale for therapeutic strategies aimed at restoring tumor-specific MHC class II expression to salvage AML relapse post-alloSCT and also potentially to enhance immunotherapy outcomes in non-myeloid malignancies.
2022-10-02 | GSE189767 | GEO