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p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment

Oncogene volume 29, pages 3942–3952 (2010)Cite this article

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Abstract

A number of drugs developed against cancer-specific molecular targets have been shown to offer survival benefits alone or in combination with standard treatments, especially for those cases in which tumor pathogenesis is dominated by a single molecular abnormality. One example for such a tumor type is alveolar rhabdomyosarcoma (aRMS), which is characterized by a specific translocation creating the oncogenic PAX3/FKHR transcription factor, believed to be the molecular basis of the disease. Recently, we were able to show that the small molecule inhibitor PKC412 (midostaurin) shows strong antitumor activity against aRMS by reducing the transcriptional activity of PAX3/FKHR. In this study, we screened for combination strategies that are superior to PKC412-only treatment and found that the combination of PKC412 with histone deacetylase inhibitors like valproic acid (VPA) synergistically induced apoptosis resulting in suppressed aRMS tumor growth in vivo. We provide evidence that the antitumor effect on combination treatment is achieved by VPA-induced reactivation of p21, which is downregulated in aRMS cells by destabilization of the transcriptional regulator EGR1 by PAX3/FKHR. Our study highlights a possible mechanism behind the increased efficacy and indicates that different arms of PAX3/FKHR oncogenicity can be exploited therapeutically by the specific combination of drugs to increase their therapeutic potential.

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Acknowledgements

We thank professor Soon Young Shin for providing constructs encoding EGR1 and p21 luciferase reporter plasmid, Silvia Behnke for her help with the stainings of tumor sections and Sarah Steinbacher for her graphical support in designing Figure 6. This work was supported by grants (3100–109837 and 3100–122562) from the Swiss National Science Foundation (SNF).

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  1. Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland

    R M Hecker, R A Amstutz, M Wachtel, D Walter, F K Niggli & B W Schäfer

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  1. R M Hecker
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  2. R A Amstutz
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  3. M Wachtel
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  4. D Walter
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  5. F K Niggli
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  6. B W Schäfer
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Correspondence to B W Schäfer.

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Hecker, R., Amstutz, R., Wachtel, M. et al. p21 Downregulation is an important component of PAX3/FKHR oncogenicity and its reactivation by HDAC inhibitors enhances combination treatment. Oncogene 29, 3942–3952 (2010). https://doi.org/10.1038/onc.2010.145

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