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

Research output: Contribution to journalArticle

26 Citations (Scopus)

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. The SPOP gene, which encodes an E3 ubiquitin ligase adaptor, is mutated in a number of cancer types. Zhu et al. show that SPOP promotes senescence, a tumor suppression mechanism, by degrading the SENP7 deSUMOylase. This correlates with HP1α-associated epigenetic gene silencing through a relay of ubiquitination and sumoylation post-transcriptional modifications.

Original languageEnglish (US)
Pages (from-to)1183-1193
Number of pages11
JournalCell Reports
Volume13
Issue number6
DOIs
StatePublished - Nov 10 2015

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Ubiquitin-Protein Ligases
Cell Aging
Tumors
Genes
Sumoylation
Neoplasms
Gene Silencing
Degradation
Ubiquitination
Epigenomics
Ubiquitin
Prostate
Phenotype
Mutation

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Zhu, Hengrui ; Ren, Shancheng ; Bitler, Benjamin G. ; Aird, Katherine M. ; Tu, Zhigang ; Skordalakes, Emmanuel ; Zhu, Yasheng ; Yan, Jun ; Sun, Yinghao ; Zhang, Rugang. / SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase. In: Cell Reports. 2015 ; Vol. 13, No. 6. pp. 1183-1193.
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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. The SPOP gene, which encodes an E3 ubiquitin ligase adaptor, is mutated in a number of cancer types. Zhu et al. show that SPOP promotes senescence, a tumor suppression mechanism, by degrading the SENP7 deSUMOylase. This correlates with HP1α-associated epigenetic gene silencing through a relay of ubiquitination and sumoylation post-transcriptional modifications.",
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Zhu, H, Ren, S, Bitler, BG, Aird, KM, Tu, Z, Skordalakes, E, Zhu, Y, Yan, J, Sun, Y & Zhang, R 2015, 'SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase', Cell Reports, vol. 13, no. 6, pp. 1183-1193. https://doi.org/10.1016/j.celrep.2015.09.083

SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase. / Zhu, Hengrui; Ren, Shancheng; Bitler, Benjamin G.; Aird, Katherine M.; Tu, Zhigang; Skordalakes, Emmanuel; Zhu, Yasheng; Yan, Jun; Sun, Yinghao; Zhang, Rugang.

In: Cell Reports, Vol. 13, No. 6, 10.11.2015, p. 1183-1193.

Research output: Contribution to journalArticle

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T1 - SPOP E3 Ubiquitin Ligase Adaptor Promotes Cellular Senescence by Degrading the SENP7 deSUMOylase

AU - Zhu, Hengrui

AU - Ren, Shancheng

AU - Bitler, Benjamin G.

AU - Aird, Katherine M.

AU - Tu, Zhigang

AU - Skordalakes, Emmanuel

AU - Zhu, Yasheng

AU - Yan, Jun

AU - Sun, Yinghao

AU - Zhang, Rugang

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