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Mol Cell. 2015 Sep 17;59(6):904-16. doi: 10.1016/j.molcel.2015.07.025. Epub 2015 Sep 3.

Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation.

Author information

1
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
2
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
3
The Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
4
Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
5
Department of Physics, State Key Laboratory of Surface Physics, Fudan University, Shanghai 200433, China.
6
Department of Medical Informatics and Statistics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
7
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
8
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
9
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
10
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
11
Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; The Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
12
The Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Molecular Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
13
The Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
14
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: sunyh@medmail.com.cn.
15
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Urology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Mayo Clinic Cancer Center, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: huang.haojie@mayo.edu.

Abstract

SPOP mutations and TMPRSS2-ERG rearrangements occur collectively in up to 65% of human prostate cancers. Although the two events are mutually exclusive, it is unclear whether they are functionally interrelated. Here, we demonstrate that SPOP, functioning as an E3 ubiquitin ligase substrate-binding protein, promotes ubiquitination and proteasome degradation of wild-type ERG by recognizing a degron motif at the N terminus of ERG. Prostate cancer-associated SPOP mutations abrogate the SPOP-mediated degradation function on the ERG oncoprotein. Conversely, the majority of TMPRSS2-ERG fusions encode N-terminal-truncated ERG proteins that are resistant to the SPOP-mediated degradation because of degron impairment. Our findings reveal degradation resistance as a previously uncharacterized mechanism that contributes to elevation of truncated ERG proteins in prostate cancer. They also suggest that overcoming ERG resistance to SPOP-mediated degradation represents a viable strategy for treatment of prostate cancers expressing either mutated SPOP or truncated ERG.

PMID:
26344096
DOI:
10.1016/j.molcel.2015.07.025
[Indexed for MEDLINE]
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