title: SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase.
abstract: 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.
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Hengrui
authors.initials: H
authors.lastname: Zhu
authors.affiliation: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Shancheng
authors.initials: S
authors.lastname: Ren
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Benjamin G
authors.initials: BG
authors.lastname: Bitler
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Aird
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Tu
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Skordalakes
authors.affiliation: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, People's Republic of China.
authors.forename: Yasheng
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, Jiangsu 210061, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Urology, Shanghai Changhai Hospital, Second Military Medical University, Shanghai 200433, People's Republic of China. Electronic address: sunyh@medmail.com.cn.
authors.forename: Yinghao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Gene Expression and Regulation Program, The Wistar Institute, Philadelphia, PA 19104, USA. Electronic address: rzhang@wistar.org.
authors.forename: Rugang
authors.initials: R
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D002478:Cells, Cultured; D016922:Cellular Senescence; D000090266:Chromobox Protein Homolog 5; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism*; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D058207:Sumoylation
chemical_list: C000715594:CBX5 protein, human; D009687:Nuclear Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; D000090266:Chromobox Protein Homolog 5; D010450:Endopeptidases; C533959:SENP7 protein, human