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

Jian An, Shancheng Ren, Stephen J. Murphy, Sumiya Dalangood, Cunjie Chang, Xiaodong Pang, Yangyan Cui, Liguo Wang, Yunqian Pan, Xiaowei Zhang, Yasheng Zhu, Chenji Wang, Geoffrey C. Halling, Liang Cheng, William R. Sukov, R. Jeffrey Karnes, George Vasmatzis, Qing Zhang, Jun Zhang, John C. ChevilleJun Yan, Yinghao Sun, Haojie Huang

Research output: Contribution to journalArticle

72 Scopus citations

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. SPOP mutations and TMPRSS2-ERG rearrangements are two of the most prevalent genetic alterations in human prostate cancer. An et al. report that SPOP functions as a tumor suppressor in prostatic cells by promoting ERG degradation, but this function is abrogated by both SPOP mutations and the majority of TMPRSS2-ERG fusions.

Original languageEnglish (US)
Pages (from-to)904-916
Number of pages13
JournalMolecular Cell
Volume59
Issue number6
DOIs
StatePublished - Sep 17 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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    An, J., Ren, S., Murphy, S. J., Dalangood, S., Chang, C., Pang, X., Cui, Y., Wang, L., Pan, Y., Zhang, X., Zhu, Y., Wang, C., Halling, G. C., Cheng, L., Sukov, W. R., Karnes, R. J., Vasmatzis, G., Zhang, Q., Zhang, J., ... Huang, H. (2015). Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation. Molecular Cell, 59(6), 904-916. https://doi.org/10.1016/j.molcel.2015.07.025