Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer

Jean Philippe P Theurillat; Namrata D. Udeshi; Wesley J. Errington; Tanya Svinkina; Sylvan C. Baca; Marius Pop; Peter J. Wild; Mirjam Blattner; Anna C. Groner; Mark A. Rubin; Holger Moch; Gilbert G. Privé; Steven A. Carr; Levi A. Garraway

doi:10.1126/science.1250255

Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer

Jean Philippe P Theurillat, Namrata D. Udeshi, Wesley J. Errington, Tanya Svinkina, Sylvan C. Baca, Marius Pop, Peter J. Wild, Mirjam Blattner, Anna C. Groner, Mark A. Rubin, Holger Moch, Gilbert G. Privé, Steven A. Carr, Levi A. Garraway

Biomedical Engineering

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179 Scopus citations

Abstract

Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants.We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.

Original language	English (US)
Pages (from-to)	85-89
Number of pages	5
Journal	Science
Volume	346
Issue number	6205
DOIs	https://doi.org/10.1126/science.1250255
State	Published - Oct 3 2014

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Theurillat, J. P. P., Udeshi, N. D., Errington, W. J., Svinkina, T., Baca, S. C., Pop, M., Wild, P. J., Blattner, M., Groner, A. C., Rubin, M. A., Moch, H., Privé, G. G., Carr, S. A., & Garraway, L. A. (2014). Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer. Science, 346(6205), 85-89. https://doi.org/10.1126/science.1250255

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title = "Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer",

abstract = "Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants.We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.",

author = "Theurillat, {Jean Philippe P} and Udeshi, {Namrata D.} and Errington, {Wesley J.} and Tanya Svinkina and Baca, {Sylvan C.} and Marius Pop and Wild, {Peter J.} and Mirjam Blattner and Groner, {Anna C.} and Rubin, {Mark A.} and Holger Moch and Priv{\'e}, {Gilbert G.} and Carr, {Steven A.} and Garraway, {Levi A.}",

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AU - Theurillat, Jean Philippe P

AU - Udeshi, Namrata D.

AU - Errington, Wesley J.

AU - Svinkina, Tanya

AU - Baca, Sylvan C.

AU - Pop, Marius

AU - Wild, Peter J.

AU - Blattner, Mirjam

AU - Groner, Anna C.

AU - Rubin, Mark A.

AU - Moch, Holger

AU - Privé, Gilbert G.

AU - Carr, Steven A.

AU - Garraway, Levi A.

PY - 2014/10/3

Y1 - 2014/10/3

N2 - Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants.We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.

AB - Cancer genome characterization has revealed driver mutations in genes that govern ubiquitylation; however, the mechanisms by which these alterations promote tumorigenesis remain incompletely characterized. Here, we analyzed changes in the ubiquitin landscape induced by prostate cancer-associated mutations of SPOP, an E3 ubiquitin ligase substrate-binding protein. SPOP mutants impaired ubiquitylation of a subset of proteins in a dominant-negative fashion. Of these, DEK and TRIM24 emerged as effector substrates consistently up-regulated by SPOP mutants.We highlight DEK as a SPOP substrate that exhibited decreases in ubiquitylation and proteasomal degradation resulting from heteromeric complexes of wild-type and mutant SPOP protein. DEK stabilization promoted prostate epithelial cell invasion, which implicated DEK as an oncogenic effector. More generally, these results provide a framework to decipher tumorigenic mechanisms linked to dysregulated ubiquitylation.

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Ubiquitylome analysis identifies dysregulation of effector substrates in SPOP-mutant prostate cancer

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