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Systematic characterization of epigenetic modifying enzymes identifies KDM3B as a key regulator in castration resistant prostate cancer

ABSTRACT: Systematic characterization of epigenetic modifying enzymes identifies KDM3B as a key regulator in castration resistant prostate cancer

PROVIDER: PRJNA525770 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR8676840.fastq.gz	Fastqsanger.gz
	SRR8676850.fastq.gz	Fastqsanger.gz
	SRR8676860.fastq.gz	Fastqsanger.gz
	SRR8676841.fastq.gz	Fastqsanger.gz
	SRR8676851.fastq.gz	Fastqsanger.gz

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Systematic characterization of epigenetic modifying enzymes identifies KDM3B as a key regulator in castration resistant prostate cancer

Project description:Androgen deprivation therapy (ADT) is the standard care for prostate cancer patients who fail surgery and radiotherapy. While initially effective, the cancer almost always recurs into a more aggressive Castration Resistant Prostate Cancer (CRPC). Despite the existing evidence on the role of epigenetic modifiers in CRPC, only a handful of enzymes have been tested. In this study, we conducted a systematic shRNA library screen, focusing of epigenetic modifiers linked to stem-cell reprogramming, in LNCaP-abl cells, a model of CRPC. Amongst the shRNA hits, KDM3B, a histone H3K9 demethylase, was identified to have the most significant anti-proliferative effect on LNCaP-abl cells. KDM3B CRISPR/Cas9 knockout phenocopied the shRNA treatment, proving the observed phenotype was not due to shRNA off-target effects. Interestingly, this decrease in proliferation was remarkably specific to androgen-independent cells. Additionally, genetic rescue experiment showed that only enzymatically active KDM3B recovers the phenotype. No alterations in the cell cycle distribution or expression of AR downstream effectors were observed, but RNASeq revealed subtle changes in the genes expression profile for cells treated with KDM3A shRNA, including in metabolome-related enzymes such as ARG2, RDH11. However, metabolomic analysis in KDM3B knockout cells showed little change overall compared to untreated cells. Interestingly, we observed a decrease in the availability of amino acids in the absence of KDM3B which requires further investigation. Overall, our studies are the first ones to show the specificity of KDM3B in CRPC.

2020-03-16 | GSE127904 | GEO

Systematic characterization of epigenetic modifying enzymes identifies KDM3B as a key regulator in castration resistant prostate cancer

Project description:Systematic characterization of epigenetic modifying enzymes identifies KDM3B as a key regulator in castration resistant prostate cancer

| PRJNA525770 | ENA

Systematic characterization of chromatin modifying enzymes identifies KDM3B as a critical regulator in castration resistant prostate cancer.

Project description:Androgen deprivation therapy (ADT) is the standard care for prostate cancer (PCa) patients who fail surgery or radiotherapy. While initially effective, the cancer almost always recurs as a more aggressive castration resistant prostate cancer (CRPC). Previous studies have demonstrated that chromatin modifying enzymes can play a critical role in the conversion to CRPC. However, only a handful of these potential pharmacological targets have been tested. Therefore, in this study, we conducted a focused shRNA screen of chromatin modifying enzymes previously shown to be involved in cellular differentiation. We found that altering the balance between histone methylation and demethylation impacted growth and proliferation. Of all genes tested, KDM3B, a histone H3K9 demethylase, was found to have the most antiproliferative effect. These results were phenocopied with a KDM3B CRISPR/Cas9 knockout. When tested in several PCa cell lines, the decrease in proliferation was remarkably specific to androgen-independent cells. Genetic rescue experiments showed that only the enzymatically active KDM3B could recover the phenotype. Surprisingly, despite the decreased proliferation of androgen-independent cell no alterations in the cell cycle distribution were observed following KDM3B knockdown. Whole transcriptome analyses revealed changes in the gene expression profile following loss of KDM3B, including downregulation of metabolic enzymes such as ARG2 and RDH11. Metabolomic analysis of KDM3B knockout showed a decrease in several critical amino acids. Overall, our work reveals, for the first time, the specificity and the dependence of KDM3B in CRPC proliferation.

| S-EPMC7056651 | biostudies-literature

KDM3A and KDM3B maintain naïve pluripotency through regulation of alternative splicing

Project description:Histone modifying enzymes play a central role in maintaining cell identity by establishing a conducive chromatin environment for lineage specific transcription factor activity. Pluripotent embryonic stem cells (ESCs) identity is characterized by lower abundance of gene repression associated histone modifications that enables rapid response to differentiation cues. The KDM3 histone demethylase family remove the repressive histone H3 lysine 9 dimethylation (H3K9me2). Here we uncover a surprising role for the KDM3 proteins in the maintenance of the pluripotent state through post-transcriptional regulation. We find through immunoaffinity purification of the KDM3A or KDM3B interactome and proximity ligation assays that KDM3A and KDM3B interact with the RNA processing factors such as EFTUD2 and PRMT5. By generating double “degron” ESCs to degrade KDM3A and KDM3B in the rapid timescale of splicing, we find altered splicing independent of H3K9me2 status. These splicing changes partially resemble the splicing pattern of the more blastocyst like ground state of pluripotency and occurred in important chromatin and transcription factors such as Dnmt3b, Tbx3 and Tcf12. Our findings reveal non-canonical roles of histone modifying enzymes in splicing to regulate cell identity. Cells were plated, allowed to adhere overnight, then treated for four hours with dTAG-13.

2024-01-14 | GSE230341 | GEO

Spatiotemporally direct capturing global substrates of post-translational modifying enzymes in living cells

Project description:Methods for direct capturing global substrates of protein-modifying enzymes in living cells are with many challenges, and yet largely unexplored. Here, we report a strategy to directly capture substrates of protein-modifying enzymes via PTM-acceptor residue crosslinking in living cells, enabling global profiling of substrates of PTM-enzymes and validation of PTM-sites in a straightforward manner.

2023-02-22 | PXD040318 |

GwEEP - A comprehensive approach for the profiling of DNA modifying enzymes

Project description:GwEEP - A comprehensive approach for the profiling of DNA modifying enzymes

| PRJNA715106 | ENA

Discovery of novel hyperthermophilic DNA modifying enzymes using a functional genomics screen

Project description:Discovery of novel hyperthermophilic DNA modifying enzymes using a functional genomics screen

| PRJNA754396 | ENA

Global gene expression analysis of CDCP1, KDM3B, and SDC1 knockdown in human marrow stromal cells

Project description:To elucidate functions of CDCP1, KDM3B and SDC1 molecules in HS5 human marrow stromal cells, global gene expression profiles were obtained and analyzed after knocking down the gene transcripts by using siRNA technology. Global gene expression profiles were obtained from HS5 marrow stromal cells after knocking down mRNA of CDCP1, KDM3B or SDC1 by using siRNA technology.

2013-12-10 | E-GEOD-53199 | biostudies-arrayexpress

The potential role of drug transporters and amikacin modifying enzymes in M. avium

Project description:The potential role of drug transporters and amikacin modifying enzymes in M. avium

| PRJNA879212 | ENA

GwEEP - A comprehensive approach for the profiling of DNA modifying enzymes

Project description:A precise understanding of DNA methylation dynamics on a genome wide scale is of great importance for the comprehensive investigation of a variety of biological processes such as reprogramming of somatic cells to iPSCs, cell differentiation and also cancer development. To date, a complex integration of multiple and distinct genome wide data sets is required to derive the global activity of DNA modifying enzymes. We present GwEEP - Genome-wide Epigenetic Efficiency Profiling as a versatile approach to infer dynamic efficiency changes of DNA modifying enzymes at base pair resolution on a genome wide scale. GwEEP relies on genome wide oxidative Hairpin Bisulfite sequencing (HPoxBS) data sets, which are translated by a sophisticated hidden Markov model into quantitative enzyme efficiencies with reported confidence around the estimates. GwEEP in its present form predicts de novo and maintenance methylation efficiencies of Dnmts, as well as the hydroxylation efficiency of Tets but its purposefully flexible design allows to capture further oxidation processes such as formylation and carboxylation given available data in the future. Applied to a well characterized ES cell model, GwEEP precisely predicts the complex epigenetic changes following a Serum-to-2i shift i.e., (i) instant reduction in maintenance efficiency (ii) gradually decreasing de novo methylation efficiency and (iii) increasing Tet efficiencies. In addition, a complementary analysis of Tet triple knock-out ES cells confirms the previous hypothesized mutual interference of Dnmts and Tets. GwEEP is applicable to a wide range of biological samples including cell lines, but also tissues and primary cell types.

2023-03-01 | GSE169070 | GEO

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