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

Nature Cell Biology volume 8, pages 1171–1177 (2006)Cite this article

Abstract

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 NFκB-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 NFκB transcription and inhibited tumour necrosis factor (TNF)α-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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Figure 1: BCA3 is modified by NEDD8 in vivo.
Figure 2: BCA3 inhibits TNFα-induced NFκB-dependent transcription in a neddylation-dependent manner.
Figure 3: BCA3 recruits the class III deacetylase SIRT1 in a neddylation-dependent manner.
Figure 4: BCA3 enhances TNFα-induced apoptosis in DU145 cells in a neddylation-dependent fashion.
Figure 5: The effect of BCA3 on TNFα-induced apoptosis in DU145 cells is dependent on SIRT1.

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Acknowledgements

This work was supported by the National Institutes of Health (NIH) R01 CA 80089 to E.T.H.Y, National Natural Science Foundation of China (30400237) to F.G. and CA-16672 (M.D. Anderson Cancer Center; MDACC).

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Authors and Affiliations

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

    Fei Gao, Jinke Cheng & Edward T. H. Yeh

  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, 77030, TX, USA

    Fei Gao & Edward T. H. Yeh

  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, 200025, China

    Fei Gao

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

    Tong Shi

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Contributions

F.G., J.C. and E.T.H.Y. conceived and designed the experiments. F.G. and T.S. performed the experiments. F.G. and E.T.H.Y wrote the paper.

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Correspondence to Edward T. H. Yeh.

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Gao, F., Cheng, J., Shi, T. et al. Neddylation of a breast cancer-associated protein recruits a class III histone deacetylase that represses NFκB-dependent transcription. Nat Cell Biol 8, 1171–1177 (2006). https://doi.org/10.1038/ncb1483

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