Two paths for stabilization of ERG in prostate carcinogenesis: TMPRSS2-ERG fusions and speckle-type pox virus and zinc finger protein mutations

mutation or TMPRSS2‐ERG fusions induced proliferation and invasion in prostate cancer cells. This study along with a recently published similar report provides two previously unrecognized mechanisms for the upregulation of ERG proteins frequently observed in prostate cancers. These findings generate great enthusiasm for the development of targeted therapeutic strategies designed to eliminate ERG protein in prostate cancer cells. SPOP is a substrate-binding adaptor protein for the Cullin-RING E3 ubiquitin l igase, which cata lyzes the speci f ic ubiquitination and proteasome degradation of multiple target proteins. Mutations in SPOP frequently appear in prostate cancer1 but do not co-occur with other prostate cancer-associated gene mutations or TMPRSS2-ERG fusions2,3 and appear to be quite rare in other cancers.4 The SPOP-Cullin 3-RING box 1 ubiquitin ligase complex binds to its substrates through the N-terminal MATH domain of the SPOP protein. Somatic SPOP mutations in prostate cancer reported thus far have all clustered in the MATH domain, potentially impacting substrate-binding. Furthermore, SPOP substrate proteins, which include Macro H2A, Puc, Daxx, and Gli, are characterized by an SPOP-binding consensus motif 1 and any alteration of the substrate-binding complex (SBC) might also impair SPOP-binding to its substrates. In a previous study, An et al. performed a protein motif search for SPOP-binding motifs in androgen receptor and ERG proteins. They initially reported that SPOP could bind to the hinge domain of the androgen receptor (AR), S POZ (pox virus and zinc finger protein) protein (SPOP) is an E3 ubiquitin ligase adaptor protein that specifically promotes the ubiquitination and proteasome degradation of proteins. SPOP mutations are frequent in prostate cancer, and in a previous study, An et al. demonstrated that SPOP induced the degradation of the androgen receptor (AR) suggesting that SPOP is important in maintaining prostate homeostasis. In this current highlighted report, An and colleagues showed that ERG, which has been implicated as an oncoprotein in prostate cancer, contains putative SPOP‐binding consensus (SBC) motifs 42ASSSS46 and 423VTSSS427 in the N‐ and C‐terminal of ERG, respectively. The authors went on to demonstrate that SPOP promotes the ubiquitination and degradation of ERG through binding to the degron/SBC motif at the ERG N‐terminus. SPOP mutations in the MATH domain prevented recognition and targeting of ERG for ubiquitination and degradation. In addition, N‐terminal truncated ERG proteins encoded by the most frequently identified TMPRSS2‐ERG rearrangements in prostate cancer (T1‐E4 and T1‐E5) were resistant to SPOP‐mediated degradation, resulting in the stabilization of truncated ERG proteins. Stabilization of ERG protein through either SPOP INVITED RESEARCH HIGHLIGHT