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

Abstract

Speckle-type 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 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.

Figure 1

Two paths for stabilization of ERG in prostate cancer. Model depicting paths for the resistance of ERG ubiquitination and degradation by the SPOP-Cullin 3-RING box 1 ubiquitin ligase complex. ERG protein is targeted for ubiquitination and degradation by SPOP through its SBC binding to the MATH domain of SPOP. Casein kinase 1 δ (CKIδ) phosphorylation of ERG facilitates the interaction between SPOP and ERG. Overexpression of ERG in prostate cancers could be due to two independent mechanisms: (1) Truncated ERG proteins due to TMPRSS2-ERG fusions not expressing the SBC are stabilized. (2) SPOP mutations in the MATH domain prevent the binding of SPOP to full wild-type ERG protein, preventing ubiquitination, and degradation. SBC: substrate-binding complex.