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PHF19 Promotes Cell Growth and Confers Drug Resistance through EZH2 Phosphorylation in Multiple Myeloma

ABSTRACT: PHF19 Promotes Cell Growth and Confers Drug Resistance through EZH2 Phosphorylation in Multiple Myeloma

PROVIDER: PRJNA527460 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8735480_1.fastq.gz	Fastqsanger.gz
	SRR8735480_2.fastq.gz	Fastqsanger.gz
	SRR8735481_1.fastq.gz	Fastqsanger.gz
	SRR8735481_2.fastq.gz	Fastqsanger.gz
	SRR8735482_1.fastq.gz	Fastqsanger.gz

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PHF19 Promotes Cell Growth and Confers Drug Resistance through EZH2 Phosphorylation in Multiple Myeloma

Project description:To determine the effect of overexpression PHF19 in ARP1 myeloma cells Drug resistance is a major reason for the recurrence of multiple myeloma (MM). In addition to genetic mutations, epigenetic abnormalities are involved in the whole process of MM relapse and drug resistance. In this study, we investigate the roles of polycomb like protein 19 (PHF19), a critical gene involved in the epigenetic regulation of gene expression, in the development of MM. The gene expression profiling (GEP) data shows that PHF19 is significantly up-regulated in MM cells and associated with shortened progression-free survival and overall survival in MM patients. PHF19 promotes MM cell growth both in vitro and in a subcutaneous xenograft mouse model. Up-regulated PHF19 is also associated with the development of resistance to multiple drugs, including bortezomib, in MM cells. Moreover, miR-15a can directly target PHF19 by binding to its 3'-UTR. Since miR-15a is down-regulated in MM cells, PHF19 is considered to be up-regulated due to loss of the suppression by miR-15a. The mechanistic investigations indicate that PHF19 can activate AKT which in turn leads to an increase in the phosphorylation of EZH2, a core component of PRC2 that mediates the histone H3K27 methylation. Subsequently suppresses histone H3K27 methylation and causes up-regulated expression of several anti-apoptotic genes, including BCL-xL, MCL-1 and HIF-1alpha. Moreover, PDK1 activation is significantly increased in PHF19 overexpressing MM cells.

2020-03-31 | GSE128406 | GEO

The role of PHF19 in promoting H3K27me3 deposition in multiple myeloma (ChIP-seq)

Project description:We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19, also known as Polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. ChIP-Seq profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains possibly due to impaired H3K27me3 spreading from CpG islands

2019-08-31 | GSE135890 | GEO

The role of PHF19 in promoting H3K27me3 deposition in multiple myeloma (RNA-Seq)

Project description:Dysregulation of Polycomb Repressive Complex 2 (PRC2) promotes oncogenesis partly through its enzymatic function for inducing tri-methylation of histone H3 lysine 27 (H3K27me3). However, it remains to be determined how PRC2 activity is regulated in normal and diseased settings. We here report a PRC2-associated cofactor, PHD finger protein 19 (PHF19, also known as Polycomb-like 3), as a crucial mediator of tumorigenicity in multiple myeloma (MM). Overexpression and/or genomic amplification of PHF19 is found associated with malignant progression of MM and plasma cell leukemia, correlating to worse treatment outcomes. Using various MM models, we demonstrated a critical requirement of PHF19 for tumor growth in vitro and in vivo. Mechanistically, PHF19-mediated oncogenic effect relies on its PRC2-interacting and chromatin-binding functions. ChIP-Seq profiling showed a critical role for PHF19 in maintaining the H3K27me3 landscape. PHF19 depletion led to loss of broad H3K27me3 domains possibly due to impaired H3K27me3 spreading from CpG islands, which is reminiscent to the reported effect of an ‘onco’-histone mutation, H3K27-to-methionine (H3K27M). RNA-Seq-based transcriptome profiling in MM lines also demonstrated a requirement of PHF19 for optimal silencing of PRC2 targets, which include cell cycle inhibitors and interferon-JAK-STAT signaling genes critically involved in tumor suppression.

2019-08-31 | GSE136410 | GEO

MMSET alters EZH2 Binding in Myeloma Cells

Project description:We investigated EZH2 binding in the presence and absence of MMSET protein. MMSET overexpression in t(4;14)+ myeloma leads to global loss of H3K27 methylation and redistribution of EZH2 binding throughout the genome ChIP-seq for EZH2 in two cell types

2014-09-01 | E-GEOD-57632 | biostudies-arrayexpress

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

MMSET alters EZH2 Binding in Myeloma Cells

2014-09-01 | GSE57632 | GEO

Effect of overexpression of PHF19 in multiple myeloma cells [RNA-seq]

Project description:To investigate the transcriptomic effect of PHF19 overexpression in MM cells. We then performed gene expression profiling analysis using data obtained from RNA-seq of AMO1 cells with differential PHF19 expression.

2023-01-31 | GSE224200 | GEO

Effect of T350 phosphorylation on gene repression activity of EZH2 in BJ cells

Project description:The Polycomb group (PcG) protein enhancer of zeste homolog 2 (EZH2) plays an essential role in histone methylation-mediated epigenetic gene silencing. We demonstrate that under physiological conditions, cyclin-dependent kinase 1 (CDK1) and 2 (CDK2) bind to and phosphorylate EZH2 at threonine 350 (T350) in an evolutionally conserved motif. T350 phosphorylation is required for EZH2 function in silencing of genes that promote differentiation and inhibit proliferation and migration. Blockage of T350 phosphorylation by generating a T350A mutation largely diminishes the global effect of EZH2 on gene silencing. Four experiments have been designed. BJ cells were transfected with si-Control, si-EZH2, si-EZH2 plus RNAi resistant lentivirus expressed EZH2, or si-EZH2 plus RNAi resistant lentivirus expressed T350A mutant for 60 hours. Each experiment was triplicated.

2010-11-10 | E-GEOD-22427 | biostudies-arrayexpress

Treatment of multiple myeloma cells with EZH2 small molecule inhibitor

Project description:We investigated differential gene expression in response to treatment of multiple myeloma cells with EZH2 inhibitor RNA-seq in two cell lines

2014-09-01 | E-GEOD-57478 | biostudies-arrayexpress

Treatment of multiple myeloma cells with EZH2 small molecule inhibitor

Project description:We investigated differential gene expression in response to treatment of multiple myeloma cells with EZH2 inhibitor

2014-09-01 | GSE57478 | GEO