VPRBP, a novel androgen receptor and OGT target is an essential mediator of cellular transformation in prostate cancer
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ABSTRACT:
PROVIDER: PRJNA715249 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13995123.fastq.gz | Fastqsanger.gz | |||
| SRR13995124.fastq.gz | Fastqsanger.gz | |||
| SRR13995125.fastq.gz | Fastqsanger.gz | |||
| SRR13995126.fastq.gz | Fastqsanger.gz | |||
| SRR13995127.fastq.gz | Fastqsanger.gz |
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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
Project description:Bone remodeling is a continuous and balanced process which relies on the dynamic equilibrium between osteoclastic bone resorption and osteoblastic bone formation. During osteoclast differentiation, pro-osteoclastogenic and anti-osteoclastogenic genes are selectively targeted by positive and negative transcription regulators, respectively. VprBP, also known as DCAF1, is a recently identified kinase and plays an important role in driving epigenetic gene silencing and oncogenic transformation. However, nothing is currently known about a possible involvement of VprBP in signaling pathways that regulates other cellular processes. Here, we demonstrate that VprBP stimulates RANKL-induced osteoclast differentiation by attenuating the expression of anti-osteoclastogenic genes through phosphorylating histone H2A at threonine 120 (H2AT120p). H2AT120p is critical for VprBP function, because abrogating VprBP kinase activity toward H2AT120 significantly attenuates the differentiation of osteoclast precursor cells (OCPs) into mature osteoclasts. Consistent with this notion, our in vivo studies established the importance of VprBP-mediated H2AT120p in low bone mass phenotypes and osteoporosis caused by overactive osteoclasts. Together, our data reveal a previously unrecognized function of VprBP in supporting osteoclast differentiation and the molecular mechanism underlying its action as a negative regulator of anti-osteoclastogenic genes.
2025-01-28 | GSE275603 | GEO
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
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
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.
2013-11-07 | GSE50414 | GEO
Project description:Androgen receptor (AR) is a major driver of prostate cancer initiation and progression. O-GlcNAc transferase (OGT), the enzyme that catalyzes the covalent addition of UDP-N-acetylglucosamine (UDP-GlcNAc) to serine and threonine residues of proteins, is often highly expressed in prostate cancer with its expression correlated with high Gleason score. In this study, we have identified an AR and OGT coregulated factor, Vpr (HIV-1) binding protein (VPRBP) also known as DDB1 and CUL4 Associated Factor 1 (DCAF1). We show that VPRBP is regulated by the AR at the transcript level, and stabilized by OGT at the protein level. VPRBP knockdown in prostate cancer cells led to a significant decrease in cell proliferation, p53 stabilization, nucleolar fragmentation, and increased p53 recruitment to the chromatin. In human prostate tumor samples, VPRBP protein overexpression correlated with AR amplification, OGT overexpression, a shorter time to postoperative biochemical progression and poor clinical outcome. In clinical transcriptomic data, VPRBP expression was positively correlated with the AR and also with AR activity gene signatures.ImplicationsIn conclusion, we have shown that VPRBP/DCAF1 promotes prostate cancer cell proliferation by restraining p53 activation under the influence of the AR and OGT.
| S-EPMC9381113 | biostudies-literature
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
Project description:TET2 directly interacts with OGT, which is important for the chromatin association of OGT in vivo. Although this specific interaction does not regulate the enzymatic activity of TET2, it facilitates OGT-dependent histone O-GlcNAcylation. Moreover, OGT associates with TET2 at transcription starting sites (TSS). Down-regulation of TET2 reduces the amount of H2B S112 GlcNAc marks in vivo, which are associated with gene transcription regulation. We found that OGT interacts with TET2 tightly. Using ChIP-seq with specific antibodies, we tested the co-localization of TET2 and OGT in genome level.
2012-12-11 | E-GEOD-41720 | biostudies-arrayexpress
Project description:Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development, function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is mediated by androgen responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell-like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous de-differentiation. It provides an innovative mechanism for castration resistance and highlights novel therapeutic strategies to treat advanced prostate cancer. Keywords: Genetic Modification compare gene expression in different cell lines with or without androgen treatment or EZH2 knockdown
2011-12-11 | E-GEOD-31978 | biostudies-arrayexpress
Project description:Androgen receptor (AR) is a hormone-activated transcription factor that plays important roles in prostate development, function, as well as malignant transformation. The downstream pathways of AR, however, are incompletely understood. AR has been primarily known as a transcriptional activator inducing prostate-specific gene expression. Through integrative analysis of genome-wide AR occupancy and androgen-regulated gene expression, here we report AR as a globally acting transcriptional repressor. This repression is mediated by androgen responsive elements (ARE) and dictated by Polycomb group protein EZH2 and repressive chromatin remodeling. In embryonic stem cells, AR-repressed genes are occupied by EZH2 and harbor bivalent H3K4me3 and H3K27me3 modifications that are characteristic of differentiation regulators, the silencing of which maintains the undifferentiated state. Concordantly, these genes are silenced in castration-resistant prostate cancer rendering a stem cell-like lack of differentiation and tumor progression. Collectively, our data reveal an unexpected role of AR as a transcriptional repressor inhibiting non-prostatic differentiation and, upon excessive signaling, resulting in cancerous de-differentiation. It provides an innovative mechanism for castration resistance and highlights novel therapeutic strategies to treat advanced prostate cancer. Keywords: Genetic Modification
2011-12-11 | GSE31978 | GEO