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Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation

Oncogene volume 34, pages 4011–4017 (2015)Cite this article

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Abstract

The Polycomb group protein Bmi-1 is an essential regulator of cellular senescence and is believed to function largely through the direct repression of the Ink4a/Arf locus. However, concurrent deletion of Ink4a/Arf does not fully rescue the defects detected in Bmi-1−/− mice, indicating that additional Bmi-1 targets remain to be identified. The expression of the chromatin-associated Sin3B protein is stimulated by oncogenic stress, and is required for oncogene-induced senescence. Here we demonstrate that oncogenic stress leads to the dissociation of Bmi-1 from the Sin3B locus, resulting in increased Sin3B expression and subsequent entry into cellular senescence. Furthermore, Sin3B is required for the senescent phenotype and elevated levels of reactive oxygen species elicited upon Bmi-1 depletion. Altogether, these results identify Sin3B as a novel direct target of Bmi-1, and establish Bmi-1-driven repression of Sin3B as an essential regulator of cellular senescence.

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Acknowledgements

We are grateful to all members of the David laboratory for helpful discussions during the preparation of the manuscript. We thank Drs Sally Temple, Gabriella De Vita, Goberdhan Dimri, David Levy and Marty McMahon for the generous gifts of plasmids used in this study and Dr Michael Garabedian for helpful discussions. We wish to acknowledge the Skirball Institute of Biomolecular Medicine for hosting our laboratory following Hurricane Sandy. All animal experiments were done in accordance with the guidelines of the National Institutes of Health (NIH) and were approved by the NYU School of Medicine Institutional Animal Care and Use Committee. This work was funded by the American Cancer Society (115014-RSG-08-054-01-GMC to DG), the National Institute of Health (5R01CA148639 and 5R21CA155736 to DG), the Irma T. Hirschl Charitable Trust (DG), the Samuel Waxman Cancer Research Foundation (DG) and a Feinberg NYU individual grant (DG). DT, CDJ and BAJ were supported by predoctoral NIH training grants T32CA009161 (DT, CDJ) and T32GM066704 (BAJ).

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  1. T DiMauro and D J Cantor: These authors contributed equally to this work.

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  1. Department of Biochemistry and Molecular Pharmacology and NYU Cancer Institute, New York University School of Medicine, New York, NY, USA

    T DiMauro, D J Cantor, A J Bainor & G David

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Correspondence to G David.

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DiMauro, T., Cantor, D., Bainor, A. et al. Transcriptional repression of Sin3B by Bmi-1 prevents cellular senescence and is relieved by oncogene activation. Oncogene 34, 4011–4017 (2015). https://doi.org/10.1038/onc.2014.322

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