Journal
MOLECULAR CELL
Volume 59, Issue 6, Pages 904-916Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2015.07.025
Keywords
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Funding
- National Institutes of Health [CA134514, CA130908]
- Department of Defense [W81XWH-09-1-622, W81XWH-14-1-0486]
- Mayo Clinic CIM Biomarker Discovery Program
- T. J. Martell Foundation Young Investigators Award
- Program for Changjiang Scholars [IRT1111]
- National Basic Research Program of China [2012CB518300]
- National Natural Science Foundation of China [81430058, 81101946, 81472397]
- Shanghai Pujiang Program [12PJD008]
- Prostate Cancer Foundation Young Investigator Award
- Shanghai Municipal Health Outstanding Young Investigator [XYQ2013077]
- Shanghai Municipal Education Commission, and Health Bureau
- Ministry of Science and Technology of China [2011CB944104]
- NNSF of China [81172009, 81372168, 30971679, 31071264, 31271531]
- Doctoral Fund of Ministry of Education of China [20110091120028]
- National Key Scientific Program of China [2011CB943902]
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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.
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