Wang Shan, Kollipara Rahul K, Humphries Caroline G, Ma Shi-Hong, Hutchinson Ryan, Li Rui, Siddiqui Javed, Tomlins Scott A, Raj Ganesh V, Kittler Ralf
Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Department of Urology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA.
Oncotarget. 2016 Oct 4;7(40):64921-64931. doi: 10.18632/oncotarget.11915.
Ets related gene (ERG) is a transcription factor that is overexpressed in 40% of prostate tumors due to a gene fusion between ERG and TMPRSS2. Because ERG functions as a driver of prostate carcinogenesis, understanding the mechanisms that influence its turnover may provide new molecular handles to target the protein. Previously, we found that ERG undergoes ubiquitination and then is deubiquitinated by USP9X in prostate cancer cells to prevent its proteasomal degradation. Here, we identify Tripartite motif-containing protein 25 (TRIM25) as the E3 ubiquitin ligase that ubiquitinates the protein prior to its degradation. TRIM25 binds full-length ERG, and it also binds the N-terminally truncated variants of ERG that are expressed in tumors with TMPRSS2-ERG fusions. We demonstrate that TRIM25 polyubiquitinates ERG in vitro and that inactivation of TRIM25 resulted in reduced polyubiquitination and stabilization of ERG. TRIM25 mRNA and protein expression was increased in ERG rearrangement-positive prostate cancer specimens, and we provide evidence that ERG upregulates TRIM25 expression. Thus, overexpression of ERG in prostate cancer may cause an increase in TRIM25 activity, which is mitigated by the expression of the deubiquitinase USP9X, which is required to stabilize ERG.
ETS相关基因（ERG）是一种转录因子，由于ERG与跨膜丝氨酸蛋白酶2（TMPRSS2）之间的基因融合，在40%的前列腺肿瘤中过表达。由于ERG作为前列腺癌发生的驱动因子，了解影响其周转的机制可能为靶向该蛋白提供新的分子靶点。此前，我们发现ERG在前列腺癌细胞中发生泛素化，然后被泛素特异性蛋白酶9X（USP9X）去泛素化，以防止其蛋白酶体降解。在这里，我们确定含三联基序蛋白25（TRIM25）为在其降解之前使该蛋白泛素化的E3泛素连接酶。TRIM25结合全长ERG，它也结合在具有TMPRSS2-ERG融合基因的肿瘤中表达且N端截短的ERG变体。我们证明TRIM25在体外使ERG多聚泛素化，并且TRIM25失活导致ERG的多聚泛素化减少和稳定性增加。TRIM25 mRNA和蛋白表达在ERG重排阳性前列腺癌标本中增加，并且我们提供证据表明ERG上调TRIM25表达。因此，ERG在前列腺癌中的过表达可能导致TRIM25活性增加，这被去泛素酶USP9X稳定ERG所需的表达所缓解。
