Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFB-dependent transcription

Fei Gao^1, 2, 3, Jinke Cheng¹, Tong Shi⁴ & Edward T. H. Yeh^1, 2

¹  Department of Cardiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 449, Houston, TX 77030, USA.

²  Research Center for Cardiovascular Diseases, Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases, The University of Texas-Houston Health Science Center Houston, TX 77030, USA.

³  Department of Cell Biology, Key Laboratory of Cell Differentiation and Apoptosis of Ministry of Education of China, Shanghai Jiao-Tong University School of Medicine, Shanghai, China 200025.

⁴  Ren-Ji Hospital, Shanghai Institute of Digestive Disease, Shanghai Jiao-Tong University School of Medicine, Shanghai, China 200001.

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 NFB-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 NFB transcription and inhibited tumour necrosis factor (TNF)-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.

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