Data Entry Maintenance

Metadata Commons Identifier

HMC000115

Project Title

Identification of Selective SWI/SNF Dependencies in Enzalutamide-Resistant Prostate Cancer

Project Description

Enzalutamide (ENZA) is a potent second-generation antiandrogen commonly used to treat hormone-sensitive and castration-resistant prostate cancer (CRPC) patients. While initially effective, the response is only temporary and the disease almost always develops resistance. Given that many ENZA-resistant tumors are not driven by specific somatic mutations, there is increasing evidence that epigenetic factors can cause ENZA resistance. To explore how resistance arises we systematically tested all the epigenetic modifiers in castration-resistant and ENZA-resistant prostate cancer models using a custom epigenetic CRISPR library. From this, we identified and validated numerous epigenetic modifiers that were selectivity essential including SMARCC2, a core component of the SWI/SNF complex (or BAF complex) that regulates gene expression by altering DNA accessibility. Additionally, our data demonstrated canonical BAF complex dependency in ENZA-resistance that was also observed following the loss of DPF2, a canonical BAF-specific component. We showed that the chromatin occupancy of SMARCC2 and BRG1 was expanded in acquired ENZA resistance to the regions that overlap with transcriptional activity and CRPC-associated transcription factors that are significantly accessible in CRPC patients. Overall, our study revealed a regulatory role for SMARCC2 in ENZA-resistant prostate cancer and demonstrated the feasibility of targeting the SWI/SNF complex in late-stage PCa. GEO record of SMARCC2 <span style="-webkit-text-stroke-width:0px;display:inline !important;float:none;font-family:Verdana, Arial, Helvetica, sans-serif;font-size:12px;font-style:normal;font-variant-caps:normal;font-variant-ligatures:normal;font-weight:400;letter-spacing:normal;orphans:2;text-align:justify;text-decoration-color:initial;text-decoration-style:initial;text-decoration-thickness:initial;text-indent:0px;text-transform:none;white-space:normal;widows:2;word-spacing:0px;">ChIP-seq and BRG1 ChIP-seq datasets: <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280839">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE280839 </a> GEO record of CRISPR screen: <a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE284210">https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE284210</a>)ATAC-seq datasets<a href="https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE156291">,</a> exome sequencing, and RNA-seq from other studies have been integrated into the analysis (https://pubmed.ncbi.nlm.nih.gov/39905188)

Project Funder(s)

AstraZeneca, TUBITAK, Royal Society Newton Advanced Fellowship

Project Institution(s)

Vancouver Prostate Centre

Project Investigator(s)

Tunc Morova, Umut Berkay Altintas, Bengul Gokbayrak, Nathan Lack

Data Access Request URL*

Keywords

ENZA resistance, SWI-SNF complex, SMARCC2, epigenomics, CRISPR, prostate cancer

Publication Link

https://pubmed.ncbi.nlm.nih.gov/39905188

Study Completed

Cohort Name

ENZA sensitive and resistant cell-lines

Cohort Size

Disease/Condition Studied

prostate cancer

Enrollment Time Window

Biobanking Consent Available

Medical History Available

Ethnicity Availability

Time Course

Patient Phenotypes

Patient Outcomes

Clinical Data Types Available

Time Course Data Points

Enrollment City

Groups

Project

Cohort

Enrollment City

Groups

Samples and Omics