BET bromodomain-mediated interaction between ERG and BRD4 promotes prostate cancer cell invasion

Alexandra M Blee,Shujun Liu,Haojie Huang,Liguo Wang

doi:10.18632/oncotarget.9513

Alexandra M Blee, Shujun Liu + Show 2 more

Open Access

https://doi.org/10.18632/oncotarget.9513

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Journal: Oncotarget	Publication Date: May 20, 2016
Citations: 44	License type: CC BY 2.5

Affiliation: University of Minnesota, Mayo Clinic

Abstract

Prostate cancer (PCa) that becomes resistant to hormone castration and next-generation androgen receptor (AR)-targeted therapies, called castration-resistant prostate cancer (CRPC), poses a significant clinical challenge. A better understanding of PCa progression and key molecular mechanisms could bring novel therapies to light. One potential therapeutic target is ERG, a transcription factor aberrantly up-regulated in PCa due to chromosomal rearrangements between androgen-regulated gene TMPRSS2 and ERG. Here we show that the most common PCa-associated truncated ERG T1–E4 (ERGΔ39), encoded by fusion between TMPRSS2 exon 1 and ERG exon 4, binds to bromodomain-1 (BD1) of bromodomain containing protein 4 (BRD4), a member of the bromodomain and extraterminal domain (BET) family. This interaction is partially abrogated by BET inhibitors JQ1 and iBET762. Meta-analysis of published ERG (T1–E4) and BRD4 chromatin immunoprecipitation-sequencing (ChIP-seq) data demonstrates overlap in a substantial portion of their binding sites. Gene expression profile analysis shows some ERG-BRD4 co-target genes are upregulated in CRPC compared to hormone-naïve counterparts. We provide further evidence that ERG-mediated invasion of PCa cells was significantly enhanced by an acetylation-mimicking mutation in ERG that augments the ERG-BRD4 interaction. Our findings reveal that PCa-associated ERG can interact and co-occupy with BRD4 in the genome, and suggest this druggable interaction is critical for ERG-mediated cell invasion and PCa progression.

Highlights

Current therapies for localized Prostate cancer (PCa) include surgery and radiation
These data indicate that wild-type and some PCa-associated variants of ETS-related gene (ERG) bind to bromodomain containing protein 4 (BRD4) and suggest that the 96KGGK99 motif may be important in mediating the interaction
We demonstrate that ERG and BRD4 interact in a manner dependent on bromodomain activity and ERG acetylation to affect prostatic cell behavior

Summary

Introduction

For advanced or recurrent PCa, hormone castration therapy or treatment with androgen receptor (AR) inhibitors is a standard of treatment These therapies inactivate the AR to halt transcription of androgen responsive target genes, but cancer cells often develop resistance. A frequent event in both primary and advanced PCa is the over-expression of ETS-related gene (ERG) transcription factor, which occurs in approximately half of all PCa, and much less frequently, other ETS family members such as ETV1, ETV4, and FLI1 [3,4,5]. In these cases, over-expression of N-terminally truncated ERG usually results from a chromosomal rearrangement. ERG is increasingly recognized as a key component of PCa [7,8,9,10] and represents a promising www.impactjournals.com/oncotarget target for PCa therapies, regulation of ERG functions, such as by post-translational modifications, is poorly understood

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