Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Homo sapiens

SUBMITTER: Marcin Cieslik

PROVIDER: E-GEOD-55064 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer.

Asangani Irfan A IA Dommeti Vijaya L VL Wang Xiaoju X Malik Rohit R Cieslik Marcin M Yang Rendong R Escara-Wilke June J Wilder-Romans Kari K Dhanireddy Sudheer S Engelke Carl C Iyer Mathew K MK Jing Xiaojun X Wu Yi-Mi YM Cao Xuhong X Qin Zhaohui S ZS Wang Shaomeng S Feng Felix Y FY Chinnaiyan Arul M AM

Nature 20140423 7504

Men who develop metastatic castration-resistant prostate cancer (CRPC) invariably succumb to the disease. Progression to CRPC after androgen ablation therapy is predominantly driven by deregulated androgen receptor (AR) signalling. Despite the success of recently approved therapies targeting AR signalling, such as abiraterone and second-generation anti-androgens including MDV3100 (also known as enzalutamide), durable responses are limited, presumably owing to acquired resistance. Recently, JQ1 a ...[more]

PMID: 24759320

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Project description:Purpose: to characterize epigenetic changes following Twist1 mediated Epithelial-Mesenchymal Transition in human Methods: we characterized the epigenetic and transcriptome landscapes using whole genome transcriptome analysis by RNA-seq, DNA methylation by digital restriction enzyme analysis of methylation (DREAM) and histone modifications by CHIP-seq of H3K4me3 and H3K27me3 in immortalized human mammary epithelial cells relative to cells induced to undergo EMT by Twist1. Results: EMT is accompanied by focal hypermethylation and widespread global DNA hypomethylation, predominantly within transcriptionally repressed gene bodies. At the chromatin level, the number of gene promoters marked by H3K4me3 increases by more than one fifth; H3K27me3 undergoes dynamic genomic redistribution characterized by loss at half of gene promoters and overall reduction of peak size by almost one-half. This is paralleled by increased phosphorylation of EZH2 at serine 21. Among genes with highly altered mRNA expression, 23.1% switch between H3K4me3 and H3K27me3 marks, and those point to the master EMT targets and regulators CDH1, PDGFRA and ESRP1. Strikingly, Twist1 increases the number of bivalent genes by more than two fold. Inhibition of the H3K27 methyltransferases EZH2 and EZH1, which form part of the PRC2 complex, results in blocking EMT and stemness properties. Conclusion: Our findings demonstrate that the EMT program requires epigenetic remodeling by the Polycomb/Trithorax complexes leading to increased cellular plasticity which suggests that its inhibition will prevent EMT, and the associated breast cancer metastasis. ChIPseq profiles of human mammary epithelial cells before (HMLE_parental) and after Twist1 transfection (HMLE_Twist) were generated in monolayer (HMLE_Twist2D) and sphere culture by deep sequencing using Illumina GAIIx or Illumina hiseq2000 Please note that the processed data files were generated by pooling both replicate samples after confirming the high correlation of the two replicates.

Dataset Information

Therapeutic Targeting of BET Bromodomain Proteins in Castration-Resistant Prostate Cancer

Publications

Therapeutic targeting of BET bromodomain proteins in castration-resistant prostate cancer.

Similar Datasets

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