Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Phosphorylation and stabilization of EZH2 by VprBP trigger aberrant gene silencing in colon cancer

ABSTRACT: Our recent work has shown that VprBP is overexpressed in colon cancer and phosphorylates histone H2AT120 to drive epigenetic gene inactivation and oncogenic transformation. We have extended these observations by investigating whether VprBP also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that VprBP directly phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, VprBP-mediated EZH2 phosphorylation leads to elevated levels of H3K27me3 and altered expression of growth regulatory genes in cancer cells. Furthermore, our preclinical studies using organoid and xenograft models revealed that EZH2 requires phosphorylation for its oncogenic function, which may have therapeutic implications for gene reactivation in colon cancer cells. Together, our data define a new mechanism underlying VprBP-driven colonic tumorigenesis by linking VprBP-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192489 | GEO | 2023/03/28

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

VprBP directs epigenetic gene silencing through H2A phosphorylation in colon cancer

Project description:Histone modification is aberrantly regulated in cancer and generates an unbalanced state of gene transcription. VprBP, a recently identified kinase, phosphorylates histone H2A on threonine 120 (T120) and is involved in oncogenic transcriptional dysregulation; however, its specific role in colon cancer is undefined. Here we show that VprBP is overexpressed in colon cancer and directly contributes to epigenetic gene silencing and cancer pathogenesis. Mechanistically, the observed function of VprBP is mediated through H2AT120 phosphorylation (H2AT120p)-driven transcriptional repression of growth regulatory genes, resulting in a significantly higher proliferative capacity of colon cancer cells. Our preclinical studies using organoid and xenograft models demonstrate that treatment with VprBP inhibitor B32B3 impairs colonic tumor growth by blocking H2AT120p and reactivating transcriptional program resembling that of normal cells. Collectively, our work describes VprBP as a master kinase contributing to the development and progression of colon cancer, making it a new molecular target for novel therapeutic strategies.

2021-10-06 | GSE180282 | GEO

VprBP directs epigenetic gene silencing through H2A phosphorylation in colon cancer

Project description:VprBP directs epigenetic gene silencing through H2A phosphorylation in colon cancer

| PRJNA747687 | ENA

VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation

Project description:DCAF1, also known as VprBP, is a recently identified atypical kinase and plays an important role in downregulating the transcription of tumor suppressor genes as well as increasing the risk for colon and prostate cancers. Melanoma is the most aggressive form of skin cancer arising from pigment-producing melanocytes and is often associated with dysregulation of epigenetic factors targeting histones. Here we demonstrate that DCAF1 is highly expressed and phosphorylates threonine 120 (T120) on histone H2A to drive transcriptional inactivation of growth regulatory genes in melanoma cells. As is the case for its epigenetic function in other types of cancers, DCAF1 acts to induce gene silencing program dependently of H2AT120 phosphorylation (H2AT120p). The significance of DCAF1-mediated H2AT120p is further underscored by the fact that DCAF1 knockdown- or DCAF1 inhibitor-induced lockage of H2AT120p mitigates melanoma tumor growth in xenograft models. Collectively, our results establish DCAF1-mediated H2AT120p as a key epigenetic signal for melanomagenesis and suggest the therapeutic potential of targeting DCAF1 kinase activity for effective melanoma treatment.

2023-05-05 | GSE230573 | GEO

Genome-wide expression analysis of VprBP knockdown in DU145 cells

Project description:VprBP has been implicated in transcriptionally silent chromatin formation and cell cycle regulation, but the molecular basis underlying such effects remains unclear. To investigate the role of VprBP on gene regulation, genme-wide gene expression analysis is carried out in DU145 cells expressing either control shRNA or VprBP shRNA. Total RNA was isolated from mock- or VprBP-depleted DU145 cells

2013-11-07 | E-GEOD-50414 | biostudies-arrayexpress

Genome-wide expression analysis of VprBP knockdown in DU145 cells

2013-11-07 | GSE50414 | GEO

Affinify Purification of EZH2 and phosphodeficient EZH2 identifies phosphorylation dependent interactions of EZH2

Project description:Overexpression of EZH2 in estrogen receptor negative (ER-) breast cancer promotes metastasis. EZH2 has been mainly studied as the catalytic component of the Polycomb Repressive Complex 2 (PRC2) that mediates gene repression by trimethylating histone H3 at lysine 27 (H3K27me3). However, how EZH2 drives metastasis despite the low H3K27me3 levels observed in ER- breast cancer is unknown. We have shown that in human invasive carcinomas and distant metastases, cytoplasmic EZH2 phosphorylated at T367 is significantly associated with ER- disease and low H3K27me3 levels. Here, we explore the interactome of EZH2 and of a phosphodeficient mutant EZH2_T367A. We identified novel interactors of EZH2, and identified interactions that are dependent on the phosphorylation and cellular localization of EZH2 that may play a role in EZH2 dependent metastatic progression.

2018-07-03 | PXD010073 | Pride

VPRBP, a novel androgen receptor and OGT target is an essential mediator of cellular transformation in prostate cancer

Project description:Androgen receptor (AR) plays a central role in the development of prostate cancer. Increased expression of O-GlcNAc transferase (OGT) and O-GlcNAcylation are also implicated in metastatic prostate caner. We have identified VPRBP as a novel androgen-regulated gene and the stability of the encoded protein is regulated by OGT.VPRBP downregulation led to significant decrease in cell proliferation and p53 stabilization in LNCaPs. In this study, we employed chromatin immunoprecipitation coupled with massive parallel sequencing (ChIP-seq) to identify changes in p53 binding to the genome in VPRBP knockdown LNCaPs compared to scrambled siRNA transfected control cells. Stabilization of p53 was associated increased p53 recruitment to the chromatin.

2022-09-22 | GSE169129 | GEO

IP-MS of DCAF1/VprBP interacting proteins in mouse CD4 T cells

Project description:DCAF1, also known as VprBP (HIV-1-viral-protein-r-binding-protein), is an evolutionary conserved substrate-binding subunit of CRL4 (Cul4a-Ddb1-Roc1) ubiquitin ligase complex. It is a cellular protein targeted by HIV-1 viral protein R (Vpr). DCAF1 modulates cellular response against HIV in macrophages, controls the survival and reprogramming of oocyte, and regulates G2/M transition. DCAF1 functions through diverse mechanisms including regulating protein poly-ubiquitination, mono-ubiquitination and phosphorylation. Nonetheless, whether and how DCAF1 controls the function of primary T cell, a major cell type infected by HIV, remains unknown. We found DCAF1 is required for cell size growth and cell cycle entry from quiescence. To investigate the underlying molecular mechanisms and identify the cellular factors that associate with DCAF1 in T cells, we analyzed DCAF1-interacting proteins in T cells using VprBP immunoprecipitation and mass spectrometry.

2016-01-12 | PXD003180 | Pride

Protein kinase A-mediated phosphorylation regulates STAT3 activation and oncogenic EZH2 activity

Project description:The effect of T372E-EZH2 and Wt-EZH2 overexpression on gene expression in TOV112D cells. We found in this study that Protein Kinase A phosphorylates T372-EZH2 and wanted to determine the gene expression changes brought upon this phosphorylation. We made a point mutation (T372E) that mimicked phospho T372-EZH2. The objective was to observe transcriptional changes in TOV112D cells in response to ectopic expression of Wt-EZH2 and T372E-EZH2 point mutation in TOV112D cells.

2018-06-05 | GSE108418 | GEO

Epigenetic Maintenance of Stemness and Malignancy in Peripheral Neuroectodermal Tumors by EZH2

Project description:Chromatin modifications are increasingly recognized as a key mechanism in cancer. The histone methyl-transferase Enhancer of Zeste, Drosophila, Homolog 2 (EZH2) is the enzymatic subunit of the polycomb PRC2 complex and methylates histone H3K27, thereby, mediating gene silencing. Down-regulation of EZH2 by RNA interference in ET suppressed oncogenic transformation, tumor development and metastasis in a respective mouse model. Further microarray analysis of EZH2 knock down, or functionally linked HDAC-inhibitor treatment revealed an undifferentiated reversible phenotype in ET maintained by EZH2. EZH2 suppression resulted in a generalized loss of H3K27me3 as well as an increase in H3 acetylation levels. In addition, ChIP-Chip assays for H3K27me3 identified genes that had specifically lost H3K27me3 upon EZH2 silencing. These findings suggested that stemness features are preserved via epigenetic mechanisms. Taken together, the genetic EWS-Fli1 translocation is intimately linked to global and gene specific epigenetic alterations in ET biology. EZH2 mediates neuroectodermal and endothelial embryonal tumor stem cell growth and metastasic spread induced by a translocation derived chimeric transcription factor. Keywords: PNET, Ewing Tumor Epigenetic regulation A673 transiently transfected with siRNA-EZH2 and siRNA-scrambled were harvested and Chromatin-IPs of H3K27me3 or H3 followed by microarray hybridisation were carried out. For detailed procedures see Burdach et al. Epigenetic Maintenance of Stemness and Malignancy in Peripheral Neuroectodermal Tumors by EZH2.

2010-05-18 | E-GEOD-15890 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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