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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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			Action	DRS
	SRR17311436_1.fastq.gz	Fastqsanger.gz
	SRR17311436_2.fastq.gz	Fastqsanger.gz
	SRR17311437_1.fastq.gz	Fastqsanger.gz
	SRR17311437_2.fastq.gz	Fastqsanger.gz
	SRR17311438_1.fastq.gz	Fastqsanger.gz

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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

Phosphorylation and stabilization of EZH2 by DCAF1/VprBP trigger aberrant gene silencing in colon cancer.

Project description:Our recent work has shown that DCAF1 (also known as 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 DCAF1 also phosphorylates non-histone proteins as an additional mechanism linking its kinase activity to colon cancer development. We now demonstrate that DCAF1 phosphorylates EZH2 at T367 to augment its nuclear stabilization and enzymatic activity in colon cancer cells. Consistent with this mechanistic role, DCAF1-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 mechanism underlying DCAF1-driven colonic tumorigenesis by linking DCAF1-mediated EZH2 phosphorylation to EZH2 stability that is crucial for establishing H3K27me3 and gene silencing program.

| S-EPMC10110550 | biostudies-literature

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 regulates osteoclast differentiation via histone H2A phosphorylation

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

VprBP regulates osteoclast differentiation via histone H2A phosphorylation

Project description:VprBP regulates osteoclast differentiation via histone H2A phosphorylation

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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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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

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, 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

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

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