Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFkappaB-dependent transcription.
Neddylation has an important role in ubiquitin-mediated protein degradation through modification of cullins, which are the main substrates for NEDD8 modification. Here, we show that breast cancer-associated protein 3 (BCA3) is a NEDD8 substrate. BCA3 suppressed NFkappaB-dependent transcription through its ability to bind to p65 and the cyclin D1 promoter in a neddylation-dependent manner. Transcriptional suppression mediated by BCA3 may be attributed to the ability of neddylated BCA3 to recruit SIRT1, a class III histone deacetylase. Silencing of endogenous BCA3 in DU145 and MCF7 cells enhanced NFkappaB transcription and inhibited tumour necrosis factor (TNF)alpha-induced apoptosis. Conversely, BCA3 silencing could be reversed by over-expression of wild-type BCA3 and SENP8, a NEDD8-specific protease, but not by neddylation-deficient BCA3 or a SENP8 mutant. These results provide a crucial link between neddylation and transcriptional regulation by SIRT1, a NAD-dependent histone deacetylase that prolongs life span in yeast and worms.
Gao
Fei
F
Department of Cardiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 449, Houston, TX 77030, USA.
Cheng
Jinke
J
Shi
Tong
T
Yeh
Edward T H
ET
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis; D001943:Breast Neoplasms; D019556:COS Cells; D002522:Chlorocebus aethiops; D056741:Cyclin D; D016213:Cyclins / Q000235:genetics / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism; D005260:Female; D020868:Gene Silencing; D006367:HeLa Cells; D006801:Humans; D008297:Male; D000075687:NEDD8 Protein; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011471:Prostatic Neoplasms; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
C471621:AKIP1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D056741:Cyclin D; D016213:Cyclins; D000075687:NEDD8 Protein; C082860:NEDD8 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D014452:Ubiquitins; D010450:Endopeptidases; C477008:SENP8 protein, human; C447939:SIRT1 protein, human; D056564:Sirtuin 1; D037761:Sirtuins