Tumor-promoting functions of UHRF1 in retinoblastoma
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ABSTRACT:
PROVIDER: PRJNA558806 | ENA |
REPOSITORIES: ENA
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Project description:UHRF1 (ubiquitin-like with PHD and ring finger domains 1) is an epigenetic regulator that is involved in the regulation of DNA and histone methylation and many other cellular events. The UHRF1 is frequently found to be overexpressed in various human cancers including retinoblastoma, and its overexpression has been associated with tumor-promoting effects such as inhibition of apoptosis and high metastatic potential. However, the detailed mechanisms underlying these tumor-promoting functions of UHRF1 in retinoblastoma still remain unclear. In this study, we uncovered that UHRF1 depletion in retinoblastoma cells sensitizes the cells to histone deacetylase (HDAC) inhibitors, augmenting apoptotic cell death. To understand the molecular mechanisms underlying the enhanced sensitivity to HDAC inhibitors in the UHRF1-depleted retinoblastoma cells, we performed the gene expression profiling in UHRF1-knockdown Y79 cells in comparison with control-knockdown cells by RNA-sequencing to identify differentially expressed genes. Our RNA-seq results revealed that UHRF1 depletion downregulates redox-responsive genes such as GSTA4 and TXN2, leading to increased intracellular oxidative stress and higher susceptibility to HDAC inhibitor treatment.
2020-02-10 | GSE135424 | GEO
Project description:UHRF1 (ubiquitin-like with PHD and ring finger domains 1) is an epigenetic regulator that is involved in the regulation of DNA and histone methylation and many other cellular events. The UHRF1 is frequently found to be overexpressed in various human cancers, and its overexpression has been associated with pro-tumorigenic effects such as inhibition of apoptosis and high metastatic potential. However, the molecular mechanisms underlying these pro-tumorigenic effects of UHRF1 overexpression in cancers still remain unclear. Retinoblastoma (Rb) is an intraocular tumor which arises from developing retina by biallelic inactivation of Rb1 gene. In this study, we uncovered that the UHRF1 is highly expressed in retinoblastoma, and genomes of retinoblastoma have differential DNA methylation patterns compared to those of normal retina, characterized by global hypomethylation and promoter hypermethylation at key tumor suppressor genes. Given the well-documented functions of UHRF1 in the regulation of DNA methylation, we hypothesized that the overexpressed UHRF1 may contribute to the aberrant DNA methylation in retinoblastoma genomes. To test our hypothesis, we profiled the genome-wide methylation patterns in normal retina and Y79 retinoblastoma cell line by MeDIP-seq, and then investigated how the methylation patterns in Y79 are affected by down-modulation of UHRF1. For identification of differentially methylated regions between the control and UHRF1 knockdown Y79 cells, we analysed three independent sets of sequencing data to unambiguously determine the effects of UHRF1 down-modulation on the methylome of Y79 retinoblastoma cells.
2017-03-30 | GSE92712 | 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:Modulation of the tumor promoting functions of cancer associated fibroblasts by PDE5 inhibition increases the efficacy of chemotherapy in human preclinical models of edophageal adenocarcinoma
2022-08-12 | PXD031148 | Pride
Project description:Accumulative studies indicate that DNA maintenance methylation by DNMT1 is initiated by binding of UHRF1 to replication fork. However, how UHRF1 gains access to chromatin in S phase is poorly understood. Here we report that LSH, a SNF2 family chromatin remodeler, facilitates DNA methylation in somatic cells primarily by promoting DNA methylation by DNMT1. We show that knockout of LSH in various somatic cells resulted in substantial reduction of DNA methylation, whereas knockout of DNMT3A and DNMT3B only moderately reduced the level of DNA methylation. Consistent with a role in maintenance methylation, genome-wide analysis of DNA methylation revealed a widespread reduction of DNA methylation in all genomic elements in LSH null cells. Mechanistically, we demonstrate that LSH interacts with UHRF1 but not DNMT1 and facilitates UHRF1 chromatin association, UHRF1-catalyzed H3 ubiquitination, and subsequent DNMT1 recruitment to replication fork. Notably, UHRF1 also enhances LSH association with replication fork. Thus, our study identifies LSH as an essential factor for maintenance methylation and provides novel insight into how LSH facilitates maintenance methylation.
2020-12-01 | GSE136931 | GEO
Project description:DNA methylation is an essential epigenetic mark in mammals. It controls gene expression and genome stability. Global DNA methylation pattern is abnormal in cancers. Ubiquitin like with PHD and RING finger domains 1 (UHRF1) is a key epigenetic regulator that recruits and activates DNA methyltransferase 1 (DNMT1), the methylation maintenance enzyme. UHRF1 is a proven oncogene and its overexpression transforms cells in vitro and causes cancer in animal models. Therefore, UHRF1 provides a unique entry point into the links between epigenetics and cancer. However, it is still not fully clear how UHRF1 works in cancer cells. To understand UHRF1 functions in cancer, we employed experimental strategy to use an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, whereby the degron-fused protein can be totally and rapidly degraded upon the addition of a small molecule, auxin. We chose the human CRC cell line HCT116 as our model and successfully generated UHRF1-AID and DNMT1-AID. Through this study, we made the significant discovery that UHRF1 not only regulates DNMT1, but also influences the activities of de novo methyltransferases DNMT3A and DNMT3B, as well as the active demethylase TET2.
2024-02-12 | GSE236026 | GEO
Project description:DNA methylation is an essential epigenetic mark in mammals. It controls gene expression and genome stability. Global DNA methylation pattern is abnormal in cancers. Ubiquitin like with PHD and RING finger domains 1 (UHRF1) is a key epigenetic regulator that recruits and activates DNA methyltransferase 1 (DNMT1), the methylation maintenance enzyme. UHRF1 is a proven oncogene and its overexpression transforms cells in vitro and causes cancer in animal models. Therefore, UHRF1 provides a unique entry point into the links between epigenetics and cancer. However, it is still not fully clear how UHRF1 works in cancer cells. To understand UHRF1 functions in cancer, we employed experimental strategy to use an advanced chemical/genetic system, the auxin-inducible degron (AID) technology, whereby the degron-fused protein can be totally and rapidly degraded upon the addition of a small molecule, auxin. We chose the human CRC cell line HCT116 as our model and successfully generated UHRF1-AID and DNMT1-AID. Through this study, we made the significant discovery that UHRF1 not only regulates DNMT1, but also influences the activities of de novo methyltransferases DNMT3A and DNMT3B, as well as the active demethylase TET2.
2024-02-12 | GSE249536 | GEO
Project description:It is widely believed that the molecular and cellular features of a tumor reflect its cell-of-origin and can thus provide clues about treatment targets. The retinoblastoma cell-of-origin has been debated for over a century. Here we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type–specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Importantly, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro. Our finding that retinoblastoma tumor cells express multiple neuronal differentiation programs that are normally incompatible in development suggests that the pathways that control retinal development and establish distinct cell types are perturbed during tumorigenesis. Therefore, the cell-of-origin for retinoblastoma cannot be inferred from the features of the tumor cells themselves. However, we now have a detailed understanding of the neuronal pathways that are deregulated in retinoblastoma and targeting the catecholamine and indolamine receptors or downstream components could provide useful therapeutic approaches in future studies. This example highlights the importance of comprehensive molecular, cellular and physiological characterization of human cancers with single cell resolution as we incorporate molecular targeted therapy into treatment regimens. 20 single cells isolated from primary pediatric retinoblastoma tumors were assayed to asses the within tumor consistency of expression signals
2011-06-07 | E-GEOD-29684 | biostudies-arrayexpress
Project description:It is widely believed that the molecular and cellular features of a tumor reflect its cell-of-origin and can thus provide clues about treatment targets. The retinoblastoma cell-of-origin has been debated for over a century. Here we report that human and mouse retinoblastomas have molecular, cellular, and neurochemical features of multiple cell classes, principally amacrine/horizontal interneurons, retinal progenitor cells, and photoreceptors. Importantly, single-cell gene expression array analysis showed that these multiple cell type–specific developmental programs are coexpressed in individual retinoblastoma cells, which creates a progenitor/neuronal hybrid cell. Importantly, neurotransmitter receptors, transporters, and biosynthetic enzymes are expressed in human retinoblastoma, and targeted disruption of these pathways reduces retinoblastoma growth in vivo and in vitro. Our finding that retinoblastoma tumor cells express multiple neuronal differentiation programs that are normally incompatible in development suggests that the pathways that control retinal development and establish distinct cell types are perturbed during tumorigenesis. Therefore, the cell-of-origin for retinoblastoma cannot be inferred from the features of the tumor cells themselves. However, we now have a detailed understanding of the neuronal pathways that are deregulated in retinoblastoma and targeting the catecholamine and indolamine receptors or downstream components could provide useful therapeutic approaches in future studies. This example highlights the importance of comprehensive molecular, cellular and physiological characterization of human cancers with single cell resolution as we incorporate molecular targeted therapy into treatment regimens. 55 primary pediatric retinoblastoma tumors were collected and assayed and compared to with 3 passaged xenografts and 4 RB cell lines
2011-06-07 | E-GEOD-29683 | biostudies-arrayexpress
Project description:We have generated and validated degron alleles of UHRF1 and/or DNMT1 in several human colorectal cancer cell lines. We then used genomics and bioinformatics to precisely describe he DNA demethylation dynamics in these cells, leading to the conclusion that UHRF1 maintains DNA methylation in cancer cells not only by stimulating DNMT1. Proteomics and genetics lead us to conclude that UHRF1 regulates DNMT3A, DNMT3B and TET2 activity in addition to regulating DNMT1. The tools we have developed will be valuable for future research efforts, and our results advance our understanding of cancer epigenetics, with potentially important therapeutic applications.
2024-02-12 | PXD043254 | Pride