In TMPRSS2–ERG-positive prostate tumors, ERG establishes new clusters of regulatory elements (CORE).

  • Major finding: In TMPRSS2–ERG-positive prostate tumors, ERG establishes new clusters of regulatory elements (CORE).

  • Mechanism: ERG establishes a new cis-regulatory landscape in the TMPRSS2 promoter to enhance ERG expression.

  • Impact:TMPRSS2–ERG-driven prostate tumors may be sensitive to therapeutic targeting of NOTCH signaling.

The ETS transcription factor ERG is often overexpressed in prostate cancer due to the TMPRSS2–ERG chromosomal translocation, which results in enhanced migration and invasion and suppressed luminal cell differentiation. ERG recruits the androgen receptor (AR) to chromatin at canonical and noncanonical AR binding sites to modify AR-dependent transcription. The effects of ERG overexpression on the prostate cancer chromatin landscape remain less well understood, prompting Kron, Murison, and colleagues to compare the chromatin landscapes in primary prostate tumors with and without TMPRSS2–ERG. Chromatin immunoprecipitation sequencing for acetylated histone H3 lysine 27 (H3K27ac) found that TMPRSS2–ERG-positive tumors have a distinct set of activated cis-regulatory elements (CRE), primarily enhancers, and changes in H3K27ac were associated with corresponding changes to gene expression. The CRE with increased H3K27ac in TMPRSS2–ERG-positive tumors were enriched for binding of the transcription factors AR, FOXA1, and HOXB13, as well as ERG itself. Further, ERG bound directly with FOXA1 and HOXB13 at chromatin to promote the localization of prostate cancer transcriptional machinery to new CREs and establish a TMPRSS2–ERG-specific transcriptional profile. ERG overexpression established new clusters of regulatory elements (CORE; also known as superenhancers) including a CORE that encompassed the TMPRSS2 promoter, upstream of ERG, that expanded past the breakpoint into ERG to promote ERG expression. ERG also activated CREs associated with NOTCH pathway genes to activate NOTCH signaling, suggesting the possibility for therapeutic targeting of NOTCH in TMPRSS2–ERG-positive tumors. Accordingly, TMPRSS2–ERG-positive cells were sensitive to NOTCH inhibition. The characterization of the cis-regulatory landscape of TMPRSS2–ERG-positive prostate tumors highlights a dependency on NOTCH signaling. Thus, NOTCH inhibitors may indirectly target ERG activity to suppress TMPRSS2–ERG-positive prostate tumor growth.

Kron KJ, Murison A, Zhou S, Huang V, Yamaguchi TN, Shiah YJ, et al. TMPRSS2-ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer. Nat Genet 2017;49:1336–45.

Note:Research Watch is written by Cancer Discovery editorial staff. Readers are encouraged to consult the original articles for full details. For more Research Watch, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/content/early/by/section.