title: Prostate cancer. 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.
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.|Harvard Medical School, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Jean-Philippe P
authors.initials: JP
authors.lastname: Theurillat
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Namrata D
authors.initials: ND
authors.lastname: Udeshi
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9. Canada.
authors.forename: Wesley J
authors.initials: WJ
authors.lastname: Errington
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Tanya
authors.initials: T
authors.lastname: Svinkina
authors.affiliation: Harvard Medical School, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Sylvan C
authors.initials: SC
authors.lastname: Baca
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.|Harvard Medical School, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Marius
authors.initials: M
authors.lastname: Pop
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, ZH 8091, Switzerland.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wild
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Blattner
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Anna C
authors.initials: AC
authors.lastname: Groner
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.|Institute for Precision Medicine of Weill Cornell and New York Presbyterian Hospital, New York, NY 10065.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Rubin
authors.affiliation: Institute of Surgical Pathology, University Hospital Zurich, Zurich, ZH 8091, Switzerland.
authors.forename: Holger
authors.initials: H
authors.lastname: Moch
authors.affiliation: Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.|Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9. Canada.
authors.forename: Gilbert G
authors.initials: GG
authors.lastname: Prive
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Carr
authors.affiliation: The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.|Harvard Medical School, Boston, MA 02115, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
mesh_terms: D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000378:metabolism; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D009361:Neoplasm Invasiveness; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D000075223:Poly-ADP-Ribose Binding Proteins; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination / Q000235:genetics*
chemical_list: D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; C084738:DEK protein, human; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D000075223:Poly-ADP-Ribose Binding Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; C555317:TRIM24 protein, human; D044767:Ubiquitin-Protein Ligases; D046988:Proteasome Endopeptidase Complex