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INVITED RESEARCH HIGHLIGHT
Year : 2016  |  Volume : 18  |  Issue : 4  |  Page : 594-595

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


1 Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA
2 Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232, USA

Date of Web Publication08-Jan-2016

Correspondence Address:
Laura E Pascal
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
USA
Zhou Wang
Department of Urology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232; University of Pittsburgh Cancer Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15232
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/1008-682X.168793

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How to cite this article:
Pascal LE, Wang Z. Two paths for stabilization of ERG in prostate carcinogenesis: TMPRSS2-ERG fusions and speckle-type pox virus and zinc finger protein mutations. Asian J Androl 2016;18:594-5

How to cite this URL:
Pascal LE, Wang Z. Two paths for stabilization of ERG in prostate carcinogenesis: TMPRSS2-ERG fusions and speckle-type pox virus and zinc finger protein mutations. Asian J Androl [serial online] 2016 [cited 2019 Oct 16];18:594-5. Available from: http://www.ajandrology.com/text.asp?2016/18/4/594/168793 - DOI: 10.4103/1008-682X.168793

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 42 ASSSS 46 and 423 VTSSS 427 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.

SPOP is a substrate-binding adaptor protein for the Cullin-RING E3 ubiquitin ligase, which catalyzes the specific ubiquitination and proteasome degradation of multiple target proteins. Mutations in SPOP frequently appear in prostate cancer [1] but do not co-occur with other prostate cancer-associated gene mutations or TMPRSS2-ERG fusions [2],[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), resulting in the degradation of full-length AR and inhibition of AR target genes and prostate cancer cell proliferation. [5] SPOP was unable to recognize and bind to AR variants, resulting in the degradation of AR but not AR variant proteins. In their recently published study, An and colleagues characterized the SPOP-binding motifs in ERG and explored the interaction between SPOP and ERG in prostate cancer cells.

Overexpression of ERG due to fusions between androgen-regulated TMPRSS2 gene promoter and the coding regions of ERG has been reported as the most common genomic alteration in prostate cancer. [6] Normally, ERG protein is expressed predominantly in endothelial cells and is not detected in epithelial tissues including the prostate epithelium. [7] However, the androgen responsive TMPRSS2 protein is preferentially expressed in normal prostate tissues and is overexpressed in the neoplastic prostatic epithelium. Androgen stimulation of TMPRSS2-ERG-positive cell lines has been shown to induce increased ERG expression. [6] In a recent study in Molecular Cell, [8] An and colleagues demonstrated that ERG was targeted by the SPOP-CUL3-RBX1 E3 ligase for ubiquitination in prostate cancer cells. The authors showed that ERG co-immunoprecipitates with SPOP and through knockdown and overexpression assays that SPOP regulates ERG protein levels. SPOP knockdown induced an increase in ERG protein as well as increased cell invasion, and this effect was abrogated by combined knockdown of SPOP and ERG suggesting that the increased invasion induced by SPOP knockdown was mediated by increased ERG. Furthermore, the effects of SPOP knockdown on proliferation were also inhibited by ERG knockdown in AR-positive C4-2 cells; genes co-regulated by SPOP and AR were inhibited by concurrent knockdown of SPOP and ERG. These results support previous findings that ERG acts as a "pioneer factor" for activation of AR signaling. [9] In a series of deletion mutant experiments, the authors showed that SPOP recognizes the 42 ASSSS 46 motif in ERG and binds to the MATH central groove. Mutations in the MATH domain of SPOP and TMPRSS2-ERG fusions that have been identified in prostate tumor specimens severely inhibited ERG binding to SPOP, resulting in the stabilization of ERG protein and the subsequent increase in cell proliferation and invasion. In patient specimens exhibiting TMPRSS2-ERG fusions lacking the SPOP substrate-binding complex (SBC), elevated ERG protein was observed by immunostaining analysis.

These findings coincide with those of Gan and colleagues, also published in Molecular Cell.[10] Gan and colleagues also showed that SPOP targets ERG for ubiquitination and degradation and that SPOP negatively regulates ERG-mediated cell migration and invasion. They showed that prostate cancer-associated mutations in SPOP and TMRPSS2-ERG fusions lacking the ERG N-terminal region resulted in the stabilization of ERG protein. In addition, Gan and colleagues demonstrated that SPOP-binding and degradation of ERG required casein kinase I δ (CKIδ)-mediated ERG phosphorylation at the N-terminal serine residues 44-46. Etoposide treatment stimulated CKI-dependent phosphorylation of specific TMPRSS2-ERG fusions with a masked SPOP-binding site, and wild-type ERG restored SPOP-binding and degradation of ERG in prostate cancer cells.

Cumulatively, these studies demonstrate two previously undefined potential paths that could contribute to the accumulation of ERG in prostate epithelial cells resulting in a subsequent increase in a cancer phenotype ([Figure 1]). Since it is extremely rare for SPOP mutations and TMPRSS2-ERG to appear concurrently, the restoration of SPOP-mediated degradation of ERG fusion protein is a potentially effective treatment strategy for patients with TMPRSS2-ERG fusions. Gan and colleagues demonstrate that etoposide could promote the accumulation of CKIδ and conformational change exposing degron 1, thus triggering the SPOP-mediated degradation of ERG. These studies illustrate that SPOP plays a critical role in prostate tumor suppression in part due to its targeted ubiquitination and degradation of ERG and provide promising evidence that therapies restoring this function could be effective in the treatment of prostate cancer.
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.

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  Competing Interests Top


All authors declared no competing interests.


  Acknowledgments Top


NIH R01 CA186780, Tippins Foundation (LEP).

 
  References Top

1.
Mani RS. The emerging role of speckle-type POZ protein (SPOP) in cancer development. Drug Discov Today 2014; 19: 1498-502.  Back to cited text no. 1
    
2.
Blattner M, Lee DJ, O'Reilly C, Park K, MacDonald TY, et al. SPOP mutations in prostate cancer across demographically diverse patient cohorts. Neoplasia 2014; 16: 14-20.  Back to cited text no. 2
    
3.
Barbieri CE, Baca SC, Lawrence MS, Demichelis F, Blattner M, et al. Exome sequencing identifies recurrent SPOP, FOXA1 and MED12 mutations in prostate cancer. Nat Genet 2012; 44: 685-9.  Back to cited text no. 3
    
4.
Kim MS, Kim MS, Yoo NJ, Lee SH. Somatic mutation of SPOP tumor suppressor gene is rare in breast, lung, liver cancers, and acute leukemias. APMIS 2014; 122: 164-6.  Back to cited text no. 4
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5.
An J, Wang C, Deng Y, Yu L, Huang H. Destruction of full-length androgen receptor by wild-type SPOP, but not prostate-cancer-associated mutants. Cell Rep 2014; 6: 657-69.  Back to cited text no. 5
    
6.
Tomlins SA, Rhodes DR, Perner S, Dhanasekaran SM, Mehra R, et al. Recurrent fusion of TMPRSS2 and ETS transcription factor genes in prostate cancer. Science 2005; 310: 644-8.  Back to cited text no. 6
    
7.
Sreenath TL, Dobi A, Petrovics G, Srivastava S. Oncogenic activation of ERG: a predominant mechanism in prostate cancer. J Carcinog 2011; 10: 37.  Back to cited text no. 7
    
8.
An J, Ren S, Murphy SJ, Dalangood S, Chang C, et al. Truncated ERG oncoproteins from TMPRSS2-ERG fusions are resistant to spop-mediated proteasome degradation. Mol Cell 2015; 59: 904-16.  Back to cited text no. 8
    
9.
Chen Y, Chi P, Rockowitz S, Iaquinta PJ, Shamu T, et al. ETS factors reprogram the androgen receptor cistrome and prime prostate tumorigenesis in response to PTEN loss. Nat Med 2013; 19: 1023-9.  Back to cited text no. 9
    
10.
Gan W, Dai X, Lunardi A, Li Z, Inuzuka H, et al. SPOP promotes ubiquitination and degradation of the erg oncoprotein to suppress prostate cancer progression. Mol Cell 2015; 59: 917-30.  Back to cited text no. 10
    


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