CSN5 isopeptidase activity links COP9 signalosome activation to breast cancer progression.
CSN5 has been implicated as a candidate oncogene in human breast cancers by genetic linkage with activation of the poor-prognosis, wound response gene expression signature. CSN5 is a subunit of the eight-protein COP9 signalosome, a signaling complex with multiple biochemical activities; the mechanism of CSN5 action in cancer development remains poorly understood. Here, we show that CSN5 isopeptidase activity is essential for breast epithelial transformation and progression. Amplification of CSN5 is required for transformation of primary human breast epithelial cells by defined oncogenes. The transforming effects of CSN5 require CSN subunits for assembly of the full COP9 signalosome and the isopeptidase activity of CSN5, which potentiates the transcriptional activity of MYC. Transgenic inhibition of CSN5 isopeptidase activity blocks breast cancer progression evoked by MYC and RAS in vivo. These results highlight CSN5 isopeptidase activity in breast cancer progression, suggesting it as a therapeutic target in aggressive human breast cancers.
Adler
Adam S
AS
Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California 94305, USA.
Littlepage
Laurie E
LE
Lin
Meihong
M
Kawahara
Tiara L A
TL
Wong
David J
DJ
Werb
Zena
Z
Chang
Howard Y
HY
D000818:Animals; D001943:Breast Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D000075686:COP9 Signalosome Complex; D019759:Carbon-Nitrogen Lyases / Q000378:metabolism* / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D009368:Neoplasm Transplantation; D010447:Peptide Hydrolases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D012190:Retroviridae / Q000235:genetics; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D010447:Peptide Hydrolases; C501488:COPS5 protein, human; D000075686:COP9 Signalosome Complex; D019759:Carbon-Nitrogen Lyases; C034300:isopeptidase