The isopeptidase USP2a regulates the stability of fatty acid synthase in prostate cancer.
Cellular levels of key regulatory proteins are controlled via ubiquitination and subsequent degradation. Deubiquitinating enzymes or isopeptidases can potentially prevent targeted destruction of protein substrates through deubiquitination prior to proteasomal degradation. However, only one deubiquitinating enzyme to date has been matched to a specific substrate in mammalian cells and shown to functionally modify it. Here we show that the isopeptidase USP2a (ubiquitin-specific protease-2a) interacts with and stabilizes fatty acid synthase (FAS), which is often overexpressed in biologically aggressive human tumors. Further, USP2a is androgen-regulated and overexpressed in prostate cancer, and its functional inactivation results in decreased FAS protein and enhanced apoptosis. Thus, the isopeptidase USP2a plays a critical role in prostate cancer cell survival through FAS stabilization and represents a therapeutic target in prostate cancer.
Graner
Edgard
E
Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02155 USA.
Tang
Dan
D
Rossi
Sabrina
S
Baron
Antonella
A
Migita
Toshiro
T
Weinstein
Lisa J
LJ
Lechpammer
Mirna
M
Huesken
Dieter
D
Zimmermann
Johann
J
Signoretti
Sabina
S
Loda
Massimo
M
D000728:Androgens / Q000378:metabolism*; D000818:Animals; D002846:Chromatography, Affinity; D003546:Cysteine Endopeptidases / Q000378:metabolism; D010450:Endopeptidases / Q000378:metabolism*; D064429:Fatty Acid Synthases / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008297:Male; D013058:Mass Spectrometry; D009097:Multienzyme Complexes / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000201:enzymology*; D046988:Proteasome Endopeptidase Complex; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D043222:Ubiquitin Thiolesterase
D000728:Androgens; D007527:Isoenzymes; D009097:Multienzyme Complexes; D034741:RNA, Small Interfering; D064429:Fatty Acid Synthases; D010450:Endopeptidases; C108665:USP2 protein, human; D043222:Ubiquitin Thiolesterase; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex