@article{438292bdc6ff435abf71b1839042d247,
title = "Truncated ERG Oncoproteins from TMPRSS2-ERG Fusions Are Resistant to SPOP-Mediated Proteasome Degradation",
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.",
author = "Jian An and Shancheng Ren and Murphy, {Stephen J.} and Sumiya Dalangood and Cunjie Chang and Xiaodong Pang and Yangyan Cui and Liguo Wang and Yunqian Pan and Xiaowei Zhang and Yasheng Zhu and Chenji Wang and Halling, {Geoffrey C.} and Liang Cheng and Sukov, {William R.} and Karnes, {R. Jeffrey} and George Vasmatzis and Qing Zhang and Jun Zhang and Cheville, {John C.} and Jun Yan and Yinghao Sun and Haojie Huang",
note = "Funding Information: This work was supported in part by grants from the National Institutes of Health (CA134514 and CA130908) and the Department of Defense (W81XWH-09-1-622 and W81XWH-14-1-0486 to H.H.); the Mayo Clinic CIM Biomarker Discovery Program; the T. J. Martell Foundation Young Investigators Award (to J.A.); the Program for Changjiang Scholars (No. IRT1111 to Y.S.); the National Basic Research Program of China (2012CB518300 to Y.S.); the National Natural Science Foundation of China (81430058 to Y.S., 81101946 and 81472397 to S.R.); the Shanghai Pujiang Program (12PJD008), Prostate Cancer Foundation Young Investigator Award, Shanghai Municipal Health Outstanding Young Investigator (XYQ2013077), Shanghai Municipal Education Commission, and Health Bureau funding (to S.R.); the Ministry of Science and Technology of China (2011CB944104 to J.Y.), NNSF of China (81172009 and 81372168 to J.Y., 30971679, 31071264, and 31271531 to Q.Z.), Doctoral Fund of Ministry of Education of China (20110091120028 to J.Y.); and the National Key Scientific Program of China (2011CB943902 to Q.Z.). Publisher Copyright: {\textcopyright} 2015 Elsevier Inc.",
year = "2015",
month = sep,
day = "17",
doi = "10.1016/j.molcel.2015.07.025",
language = "English (US)",
volume = "59",
pages = "904--916",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",
}