SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase
Hengrui Zhu,
Shancheng Ren,
Benjamin G. Bitler,
Katherine M. Aird,
Zhigang Tu,
Emmanuel Skordalakes,
Yasheng Zhu,
Jun Yan,
Yinghao Sun,
Rugang Zhang
Affiliations
Hengrui Zhu
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Shancheng Ren
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of China
Benjamin G. Bitler
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Katherine M. Aird
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Zhigang Tu
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Emmanuel Skordalakes
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
Yasheng Zhu
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of China
Jun Yan
MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, People’s Republic of China
Yinghao Sun
Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, People’s Republic of China
Rugang Zhang
Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA
The SPOP gene, which encodes an E3 ubiquitin ligase adaptor, is frequently mutated in a number of cancer types. However, the mechanisms by which SPOP functions as a tumor suppressor remain poorly understood. Here, we show that SPOP promotes senescence, an important tumor suppression mechanism, by targeting the SENP7 deSUMOylase for degradation. SPOP is upregulated during senescence. This correlates with ubiquitin-mediated degradation of SENP7, which promotes senescence by increasing HP1α sumoylation and the associated epigenetic gene silencing. Ectopic wild-type SPOP, but not its cancer-associated mutants, drives senescence. Conversely, SPOP knockdown overcomes senescence. These phenotypes correlate with ubiquitination and degradation of SENP7 and HP1α sumoylation, subcellular re-localization, and its associated gene silencing. Furthermore, SENP7 is expressed at higher levels in prostate tumor specimens with SPOP mutation (n = 13) compared to those with wild-type SPOP (n = 80). In summary, SPOP acts as a tumor suppressor by promoting senescence through degrading SENP7.
