Browse
Submit Data
Databases
API
Help

Dataset Information

28 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of CHD1 Promotes Heterogeneous Mechanisms of Resistance to AR-Targeted Therapy via Chromatin Dysregulation.

ABSTRACT: Metastatic prostate cancer is characterized by recurrent genomic copy number alterations that are presumed to contribute to resistance to hormone therapy. We identified CHD1 loss as a cause of antiandrogen resistance in an in vivo small hairpin RNA (shRNA) screen of 730 genes deleted in prostate cancer. ATAC-seq and RNA-seq analyses showed that CHD1 loss resulted in global changes in open and closed chromatin with associated transcriptomic changes. Integrative analysis of this data, together with CRISPR-based functional screening, identified four transcription factors (NR3C1, POU3F2, NR2F1, and TBX2) that contribute to antiandrogen resistance, with associated activation of non-luminal lineage programs. Thus, CHD1 loss results in chromatin dysregulation, thereby establishing a state of transcriptional plasticity that enables the emergence of antiandrogen resistance through heterogeneous mechanisms.

SUBMITTER: Zhang Z

PROVIDER: S-EPMC7292228 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-03-26 | GSE126918 | GEO

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [shRNA screen]

Project description:Next generation androgen receptor (AR) signaling inhibitors have significantly improved the survival of men with metastatic castration-resistant prostate cancer (mCPRC) but resistance remains a problem. Genomic alterations at the AR locus are present in ~50% of mCRPC patients, typically in association with large numbers of copy number gains and losses across the genome. To explore the functional consequences of these copy number alterations, we screened an shRNA library targeting all genes deleted in prostate cancer (the prostate cancer deletome: 4380 shRNAs targeting 730 genes) for next generation antiandrogen resistance using a clinically-validated model of enzalutamide-sensitive, AR-driven mCRPC LNCaP/AR. The Chromatin helicase DNA-binding factor (CHD1) scored as a top candidate and was validated in vitro and in vivo using multiple independent shRNAs and CRISPR guides. Mechanistically, CHD1 loss led to global changes in open and closed chromatin (ATAC-seq) as well as downregulation of canonical AR target genes upon the challenge of antiandrogen, despite robust AR expression. Integrative analysis of ATAC- and RNA-seq changes following CHD1 deletion identified 23 candidate transcription factor drivers of enzalutamide resistance. CRISPR-based unbiased functional screening identified 4 of these drivers may drive the AR-independent resistance, including glucocorticoid receptor (GR), BRN2, NR2F1 and TBX2. Genetic studies further establish that CHD1 loss confers antiandrogen resistance by converting mCRPC cells from AR-dependence to GR-dependence in one of the resistant LNCaP/AR clone. Thus, CHD1 functions as a molecular tuner to regulate chromatin plasticity and maintain oncogenic AR signaling, as well as AR dependency.

2020-03-26 | GSE127957 | GEO

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [ATAC-seq]

2020-03-26 | GSE127241 | GEO

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [RNA-seq]

2020-03-26 | GSE126917 | GEO

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer

Project description:Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer

| PRJNA523724 | ENA

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [ATAC-seq]

Project description:Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [ATAC-seq]

| PRJNA524393 | ENA

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [shRNA screen]

Project description:Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [shRNA screen]

| PRJNA525865 | ENA

Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [RNA-seq]

Project description:Loss of CHD1 promotes chromatin dysregulation leading to heterogeneous mechanisms of resistance to hormone therapy in prostate cancer [RNA-seq]

| PRJNA523728 | ENA

AKR1C3 Promotes AR-V7 Protein Stabilization and Confers Resistance to AR-Targeted Therapies in Advanced Prostate Cancer.

Project description:The mechanisms resulting in resistance to next-generation antiandrogens in castration-resistant prostate cancer are incompletely understood. Numerous studies have determined that constitutively active androgen receptor (AR) signaling or full-length AR bypass mechanisms may contribute to the resistance. Previous studies established that AKR1C3 and AR-V7 play important roles in enzalutamide and abiraterone resistance. In the present study, we found that AKR1C3 increases AR-V7 expression in resistant prostate cancer cells through enhancing protein stability via activation of the ubiquitin-mediated proteasome pathway. AKR1C3 reprograms AR signaling in enzalutamide-resistant prostate cancer cells. In addition, bioinformatical analysis of indomethacin-treated resistant cells revealed that indomethacin significantly activates the unfolded protein response, p53, and apoptosis pathways, and suppresses cell-cycle, Myc, and AR/ARV7 pathways. Targeting AKR1C3 with indomethacin significantly decreases AR/AR-V7 protein expression in vitro and in vivo through activation of the ubiquitin-mediated proteasome pathway. Our results suggest that the AKR1C3/AR-V7 complex collaboratively confers resistance to AR-targeted therapies in advanced prostate cancer.

| S-EPMC6995728 | biostudies-literature

Sequence-targeted nucleosome sliding in vivo by a hybrid Chd1 chromatin remodeler.

Project description:ATP-dependent chromatin remodelers regulate chromatin dynamics by modifying nucleosome positions and occupancy. DNA-dependent processes such as replication and transcription rely on chromatin to faithfully regulate DNA accessibility, yet how chromatin remodelers achieve well-defined nucleosome positioning in vivo is poorly understood. Here, we report a simple method for site-specifically altering nucleosome positions in live cells. By fusing the Chd1 remodeler to the DNA binding domain of the Saccharomyces cerevisiae Ume6 repressor, we have engineered a fusion remodeler that selectively positions nucleosomes on top of adjacent Ume6 binding motifs in a highly predictable and reproducible manner. Positioning of nucleosomes by the fusion remodeler recapitulates closed chromatin structure at Ume6-sensitive genes analogous to the endogenous Isw2 remodeler. Strikingly, highly precise positioning of single founder nucleosomes by either chimeric Chd1-Ume6 or endogenous Isw2 shifts phased chromatin arrays in cooperation with endogenous chromatin remodelers. Our results demonstrate feasibility of engineering precise nucleosome rearrangements through sequence-targeted chromatin remodeling and provide insight into targeted action and cooperation of endogenous chromatin remodelers in vivo.

| S-EPMC4864466 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data