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
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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