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Regulation of mitosis and taxane response by Daxx and Rassf1

Oncogene volume 31, pages 13–26 (2012)Cite this article

Abstract

Current theories suggest that mitotic checkpoint proteins are essential for proper cellular response to taxanes, a widely used family of chemotherapeutic compounds. We recently showed that absence or depletion of protein Daxx increases cellular taxol (paclitaxel) resistance—a common trait of patients diagnosed with several malignancies, including breast cancer. Further investigation of Daxx-mediated taxol response revealed that Daxx is important for the proper timing of mitosis progression and cyclin B stability. Daxx interacts with mitotic checkpoint protein RAS-association domain family protein 1 (Rassf1) and partially colocalizes with this protein during mitosis. Rassf1/Daxx depletion or expression of Daxx-binding domain of Rassf1 elevates cyclin B stability and increases taxol resistance in cells and mouse xenograft models. In breast cancer patients, we observed the inverse correlation between Daxx and clinical response to taxane-based chemotherapy. These data suggest that Daxx and Rassf1 define a mitotic stress checkpoint that enables cells to exit mitosis as micronucleated cells (and eventually die) when encountered with specific mitotic stress stimuli, including taxol. Surprisingly, depletion of Daxx or Rassf1 does not change the activity of E3 ubiquitin ligase anaphase promotion complex/C in in vitro settings, suggesting the necessity of mitotic cellular environment for proper activation of this checkpoint. Daxx and Rassf1 may become useful predictive markers for the proper selection of patients for taxane chemotherapy.

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Acknowledgements

We thank Dr Gerd Pfeifer, Beckman Research Institute, for the generous gift of anti-Rassf1 antibodies and Dr Frank Rauscher, The Wistar Institute, for HP1 antibodies. This work was supported by NIH/NCI R01 CA127378-01A1 for CRL, SG, VMM and AMI, by the Canadian Cancer Society (017308) for EE and LPM. NMR spectroscopy support was provided by the Canadian Institutes for Health Research (CIHR), the Canadian Foundation for Innovation (CFI), the British Columbia Knowledge Development Fund (BCKDF), the UBC Blusson Fund and the Michael Smith Foundation for Health Research (MSFHR).

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  1. M K Summers

    Present address: 6Current address: Lerner Research Institute Department of Cancer Biology, Cleveland, OH, USA.,

  2. S Giovinazzi and C R Lindsay: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, University of Florida Shands Cancer Center, Gainesville, FL, USA

    S Giovinazzi, C R Lindsay, V M Morozov & A M Ishov

  2. Department of Biochemistry and Molecular Biology and Department of Chemistry, University of British Columbia, Vancouver, British Columbia, Canada

    E Escobar-Cabrera & L P McIntosh

  3. Department of Cellular Regulation, Genentech Inc., South San Francisco, CA, USA

    M K Summers

  4. H Lee Moffitt Cancer Center and Research Institute, University of South Florida College of Medicine, Tampa, FL, USA

    H S Han

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Giovinazzi, S., Lindsay, C., Morozov, V. et al. Regulation of mitosis and taxane response by Daxx and Rassf1. Oncogene 31, 13–26 (2012). https://doi.org/10.1038/onc.2011.211

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