Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation.
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.
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.
Jian
J
An
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Shancheng
S
Ren
The Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Stephen J
SJ
Murphy
Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
Sumiya
S
Dalangood
Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
Cunjie
C
Chang
Department of Physics, State Key Laboratory of Surface Physics, Fudan University, Shanghai 200433, China.
Xiaodong
X
Pang
Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
Yangyan
Y
Cui
Department of Medical Informatics and Statistics, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Liguo
L
Wang
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Yunqian
Y
Pan
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Xiaowei
X
Zhang
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China.
Yasheng
Y
Zhu
State Key Laboratory of Genetic Engineering, School of Life Sciences, Fudan University, Shanghai 200433, China.
Chenji
C
Wang
The Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Geoffrey C
GC
Halling
Department of Pathology, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Liang
L
Cheng
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
William R
WR
Sukov
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.
R Jeffrey
RJ
Karnes
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.
George
G
Vasmatzis
Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
Qing
Q
Zhang
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Jun
J
Zhang
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.
John C
JC
Cheville
Model Animal Research Center, MOE Key Laboratory Model Animal for Disease Study, Nanjing University, Nanjing, Jiangsu 210061, China.
Jun
J
Yan
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, China. Electronic address: sunyh@medmail.com.cn.
Yinghao
Y
Sun
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.
Haojie
H
Huang
D000595:Amino Acid Sequence; D049109:Cell Proliferation; D056905:Chromosome Breakpoints; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000502:physiology*; D015514:Oncogene Proteins, Fusion / Q000502:physiology*; D010446:Peptide Fragments / Q000502:physiology; D011471:Prostatic Neoplasms / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D059748:Proteolysis; D012097:Repressor Proteins / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology*; D000071230:Transcriptional Regulator ERG; D054875:Ubiquitination
C072312:ERG protein, human; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D010446:Peptide Fragments; D012097:Repressor Proteins; C509761:SPOP protein, human; C515553:TMPRSS2-ERG fusion protein, human; D015534:Trans-Activators; D000071230:Transcriptional Regulator ERG; D046988:Proteasome Endopeptidase Complex