Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Analysis of DNA methylation in colorectal cancer RKO cells with UHRF1 depletion and HDAC inhibition

ABSTRACT: UHRF1 is a major regulator of epigenetic mechanism and is overexpressed in various human malignancies. In this study, we examined the involvement of UHRF1 in aberrant DNA methylation in colorectal cancer (CRC). In CRC cells, transient UHRF1 knockdown rapidly induced DNA demethylation across entire genomic regions, including CpG islands, gene bodies and repetitive elements. Nonetheless, UHRF1 depletion only minimally reversed CpG island hypermethylation-associated gene silencing. However, the combination of UHRF1 depletion and histone deacetylase (HDAC) inhibition synergistically reactivated the silenced genes and strongly suppressed CRC cell proliferation. Our results suggest that (i) maintenance of DNA methylation in CRC cells is highly dependent on UHRF1; (ii) UHRF1 depletion rapidly induces DNA demethylation, though it is insufficient to fully reactivate the silenced genes; and (iii) dual targeting of UHRF1 and HDAC may be an effective new therapeutic strategy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106438 | GEO | 2019/05/21

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Analysis of gene expression in colorectal cancer RKO cells with UHRF1 depletion and HDAC inhibition

Project description:UHRF1 is a major regulator of epigenetic mechanism and is overexpressed in various human malignancies. In this study, we examined the involvement of UHRF1 in aberrant DNA methylation in colorectal cancer (CRC). In CRC cells, transient UHRF1 knockdown rapidly induced DNA demethylation across entire genomic regions, including CpG islands, gene bodies and repetitive elements. Nonetheless, UHRF1 depletion only minimally reversed CpG island hypermethylation-associated gene silencing. However, the combination of UHRF1 depletion and histone deacetylase (HDAC) inhibition synergistically reactivated the silenced genes and strongly suppressed CRC cell proliferation. Our results suggest that (i) maintenance of DNA methylation in CRC cells is highly dependent on UHRF1; (ii) UHRF1 depletion rapidly induces DNA demethylation, though it is insufficient to fully reactivate the silenced genes; and (iii) dual targeting of UHRF1 and HDAC may be an effective new therapeutic strategy.

2019-05-21 | GSE113664 | GEO

Analysis of DNA methylation in colorectal cancer DLD1 cells with UHRF1 depletion and HDAC inhibition

2019-05-21 | GSE106437 | GEO

Analysis of gene expression in colorectal cancer DLD1 cells with UHRF1 depletion and HDAC inhibition

2019-05-21 | GSE106402 | GEO

Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties [expression]

Project description:UHRF1 is essential for targeting DNA methyltransferases (DNMT’s) to replicating DNA to establish de novo DNA methylation and maintain it. While, UHRF1 domains are defined, including requirement for an E3 ligase region, for de novo methylation, those essential for maintenance have been difficult to outline. Herein, via a new assay, chromatin histone-binding and a hemimethylated DNA reader domains, but not the ligase domain are found essential for cancer-specific DNA methylation maintenance in human colorectal cancer (CRC) cells. Disrupting each essential domain phenocopies UHRF1 depletion for global DNA demethylation, reactivation of tumor suppressor genes (TSGs), and reduction in CRC invasion and metastatic properties. Moreover, there is strong negative correlation between high UHRF1 expression, low TSG expression, and abnormal methylation with CRC progression and overall survival. Our battery of findings suggest the value of targeting specific domains of UHRF1 for cancer therapy and adding a precision medicine approach through use of the biomarker associations we define.

2019-02-28 | GSE118971 | GEO

Defining UHRF1 Domains That Support Maintenance of Human Colon Cancer DNA Methylation and Oncogenic Properties [methylation]

2019-02-28 | GSE118970 | GEO

Simultaneous silencing of Aurora-A and UHRF1 inhibits colorectal cancer cell growth by regulating the expression of DNMT1 and STAT1

Project description:Aurora-A has attracted a great deal of interest as a potential therapeutic target. However, the outcomes of inhibitors targeting Aurora-A are not as favorable as expected, and the basis of their ineffectiveness remains unknown. Here, we found that signal transducer and activator of transcription 1 (STAT1) was highly expressed in colorectal cancer (CRC) xenograft mouse models that were resistant to alisertib, an Aurora-A inhibitor, in an interferon/Janus kinase-independent manner, suggesting an unconventional mechanism regulating STAT1 expression. Unexpectedly, we found that alisertib disrupted Aurora-A binding with ubiquitin-like with plant homeodomain and ring finger domain 1 (UHRF1), leading to UHRF1-mediated ubiquitination and degradation of DNA methyltransferase 1 (DNMT1), which in turn resulted in demethylation of the CpG islands in the STAT1 promoter and STAT1 overexpression. Simultaneous silencing of Aurora-A and UHRF1 prevented STAT1 overexpression and effectively inhibited CRC growth. Hence, concomitant targeting of Aurora-A and UHRF1 can be a promising therapeutic strategy for cancer patients.

2020-10-26 | GSE160037 | GEO

Analysis of DNA methylation in colorectal cancer RKO cells with UHRF1 depletion and HDAC inhibition

Project description:Analysis of DNA methylation in colorectal cancer RKO cells with UHRF1 depletion and HDAC inhibition

| PRJNA416877 | ENA

Tumor-promoting functions of UHRF1 in retinoblastoma

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

UHRF1 depletion and HDAC inhibition synergistically reactivate epigenetically silenced genes in colorectal cancer cells

Project description:UHRF1 depletion and HDAC inhibition synergistically reactivate epigenetically silenced genes in colorectal cancer cells

| PRJNA416872 | ENA

Hemi-methylated DNA regulates DNA methylation inheritance through allosteric control of H3 ubiquitylation by UHRF1

Project description:DNA methylation is a heritable chromatin modification essential to mammalian development that functions with histone post-translational modifications to regulate chromatin structure and gene expression programs. The epigenetic inheritance of DNA methylation requires the combined actions of DNMT1 and UHRF1, a histone- and DNA-binding RING E3 ubiquitin ligase that facilitates DNMT1 recruitment to sites of newly replicated DNA through the ubiquitylation of histone H3. UHRF1 binds DNA with modest selectivity towards hemi-methylated CpG dinucleotides (HeDNA); however, the contribution of HeDNA sensing to UHRF1 function remains elusive. Here, we reveal that the interaction of UHRF1 with HeDNA is required for DNA methylation inheritance but is dispensable for chromatin interaction, which is governed by reciprocal positive cooperativity between the UHRF1 histone- and DNA-binding domains. We further show that HeDNA functions as an allosteric regulator of UHRF1 ubiquitin ligase activity, directing ubiquitylation towards multiple lysines on the H3 tail adjacent to the UHRF1 histone-binding site. Collectively, our studies define a highly orchestrated epigenetic control mechanism involving modifications both to histones and DNA that facilitate UHRF1 chromatin targeting, H3 ubiquitylation, and DNA methylation inheritance.

2016-08-25 | PXD003983 | Pride

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data