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

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

PROVIDER: PRJNA791646 | ENA |

REPOSITORIES: ENA

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

Project description: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.

2023-03-28 | GSE192489 | GEO

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/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation

Project description:VprBP/DCAF1 triggers melanomagenic gene silencing through histone H2A phosphorylation

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Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T Cell Leukemogenesis

Project description:Direct Phosphorylation and Stabilization of MYC by Aurora B Kinase Promote T Cell Leukemogenesis

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VprBP directs epigenetic gene silencing through H2A phosphorylation in colon cancer

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

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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

EZH2-dependent transcriptional complex promotes aberrant epithelial remodelling after injury

Project description:Unveiling the molecular mechanisms of tissue remodelling following injury is imperative to elucidate its regenerative capacity and aberrant repair in disease. Using different omics approaches, we identified enhancer of zester homolog 2 (EZH2) as a key regulator that initiates a fibrotic cascade in injured lung epithelium. Epithelial-injury-driven enrichment of nuclear transforming growth factor-b-activated kinase 1 (TAK1) mediates EZH2 phosphorylation to facilitate the release of EZH2 from polycomb repressive complex 2 (PRC2). This process leads to the establishment of a fibrotic transcriptional complex of EZH2, RNA-polymerase II (POL2) and nuclear actin, which orchestrates aberrant epithelial lung repair programs. The liberation of EZH2 from PRC2 is accompanied by an EZH2-EZH1 switch to preserve silencing at non-target genes. Loss of epithelial TAK1, EZH2 or blocking nuclear actin influx attenuates the fibrotic cascade and restores respiratory homeostasis. Accordingly, EZH2 inhibition significantly improves outcomes in a pulmonary fibrosis mouse model. Our results reveal an important non-canonical function of EZH2, paving the way for new therapeutic interventions in fibrotic lung diseases.

2021-04-27 | MSV000087321 | MassIVE

Aberrant Activation of β-Catenin Signaling Drives Glioma Tumorigenesis via USP1-Mediated Stabilization of EZH2.

Project description:Aberrant activation of β-catenin signaling is a critical driver for tumorigenesis, but the mechanism underlying this activation is not completely understood. In this study, we demonstrate a critical role of β-catenin signaling in stabilization of enhancer of zeste homolog 2 (EZH2) and control of EZH2-mediated gene repression in oncogenesis. β-Catenin/TCF4 activated the transcription of the deubiquitinase USP1, which then interacted with and deubiquitinated EZH2 directly. USP1-mediated stabilization of EZH2 promoted its recruitment to the promoters of CDKN1B, RUNX3, and HOXA5, resulting in enhanced enrichment of histone H3K27me3 and repression of target gene expression. In human glioma specimens, expression levels of nuclear β-catenin, USP1, and EZH2 correlated with one another. Depletion of β-catenin/USP1/EZH2 repressed glioma cell proliferation in vitro and tumor formation in vivo. Our findings indicate that a β-catenin-USP1-EZH2 axis orchestrates the interplay between dysregulated β-catenin signaling and EZH2-mediated gene epigenetic silencing during glioma tumorigenesis. SIGNIFICANCE: These findings identify the β-catenin-USP1-EZH2 signaling axis as a critical mechanism for glioma tumorigenesis that may serve as a new therapeutic target in glioblastoma.

| S-EPMC9646285 | biostudies-literature

ChipSeq of mouse embryonic fibroblasts from conditional knock-in mouse carrying a phosphorylation-deficient S180A (SA) mutation in exon 5 of the endogenous mouse Trp53 gene locus

Project description:The mouse S180A (SA) mutation of the Trp53 is a p53 phosphorylation-deficient mutant protein with native conformation. Here we want to assess the impact of DNA binding site phosphorylation of the p53 target gene spectrum and transcriptional activity under untreated conditions and following p53 stabilization with the Mdm2 inhibitor nutlin-3a.

2020-06-04 | E-MTAB-9170 | biostudies-arrayexpress

RNAseq of mouse embryonic fibroblasts from conditional knock-in mice carrying a phosphorylation-deficient S180A (SA) mutation in exon 5 of the endogenous mouse Trp53 gene locus

2020-08-25 | E-MTAB-9171 | biostudies-arrayexpress