Format

Send to

Choose Destination
Science. 2014 Oct 3;346(6205):85-89. doi: 10.1126/science.1250255. Epub 2014 Oct 2.

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

Author information

1
The Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
2
Harvard Medical School, Boston, MA 02115, USA.
3
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
4
Department of Biochemistry, University of Toronto, Toronto, Ontario M5S 1A8, Canada.
5
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, M5G 2M9. Canada.
6
Institute of Surgical Pathology, University Hospital Zurich, Zurich, ZH 8091, Switzerland.
7
Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, NY 10065, USA.
8
Institute for Precision Medicine of Weill Cornell and New York Presbyterian Hospital, New York, NY 10065.
9
Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
#
Contributed equally

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.

PMID:
25278611
PMCID:
PMC4257137
DOI:
10.1126/science.1250255
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center