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HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer

Oncogene volume 36, pages 1804–1815 (2017)Cite this article

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Abstract

Mutation of p53 is a frequent genetic lesion in pancreatic cancer being an unmet clinical challenge. Mutants of p53 have lost the tumour-suppressive functions of wild type p53. In addition, p53 mutants exert tumour-promoting functions, qualifying them as important therapeutic targets. Here, we show that the class I histone deacetylases HDAC1 and HDAC2 contribute to maintain the expression of p53 mutants in human and genetically defined murine pancreatic cancer cells. Our data reveal that the inhibition of these HDACs with small molecule HDAC inhibitors (HDACi), as well as the specific genetic elimination of HDAC1 and HDAC2, reduce the expression of mutant p53 mRNA and protein levels. We further show that HDAC1, HDAC2 and MYC directly bind to the TP53 gene and that MYC recruitment drops upon HDAC inhibitor treatment. Therefore, our results illustrate a previously unrecognized class I HDAC-dependent control of the TP53 gene and provide evidence for a contribution of MYC. A combined approach targeting HDAC1/HDAC2 and MYC may present a novel and molecularly defined strategy to target mutant p53 in pancreatic cancer.

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Acknowledgements

We thank Dr E. Olson, Dr T. Jacks, Dr A. Lowy, Dr P. Soriano, and Dr D. Tuveson for providing mouse lines. We thank Dr A. Bradley for support and help during the transfer of mouse lines. This work was supported by: Deutsche Krebshilfe [110908 to G.S., 110909 to O.H.K., and 111273 to M.R.], Wilhelm-Sander Stiftung [2016.004.1 to S.M. and G.S., 2010.078.1 to O.H.K], Else Kröner-Fresenius-Stiftung (2016_A43 to M.W.), Deutsche Forschungsgemeinschaft (DFG) [SCHN 959/2-1 to G.S.; SFB824/C9 to G.S. and D.S.; KR 2291/4-1/MA; 2183/1-1 to O.H.K. and S.M., and KR 2291/5-1 to O.H.K.], and DKTK Joint Funding [to R.R., D.S., and G.S.].

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  1. N Stojanovic, Z Hassan and M Wirth: Equal first author contribution.

  2. O H Krämer and G Schneider: Equal senior author contribution.

Authors and Affiliations

  1. II. Medizinische Klinik, Technische Universität München, München, Germany

    N Stojanovic, Z Hassan, M Wirth, P Wenzel, A Kroemer, R M Schmid, R Rad, M Reichert, D Saur & G Schneider

  2. Department of Toxicology, University of Mainz Medical Center, Mainz, Germany

    M Beyer & O H Krämer

  3. Institute of Biochemistry and Biophysics/Center for Molecular Biomedicine (CMB), Friedrich-Schiller-University Jena, Jena, Germany

    C Schäfer & P Brand

  4. Molecular and Cellular Oncology/ENT, University Medical Center Mainz, Mainz, Germany

    R H Stauber

  5. 1st Department of Internal Medicine I, Laboratory of Molecular Gastroenterology and Hepatology, University Hospital Schleswig-Holstein, Kiel, Germany

    A Arlt

  6. Department of Pharmaceutical Chemistry I, Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany

    A Sellmer & S Mahboobi

  7. German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany

    R Rad, D Saur & G Schneider

  8. Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    M Reichert

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Stojanovic, N., Hassan, Z., Wirth, M. et al. HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. Oncogene 36, 1804–1815 (2017). https://doi.org/10.1038/onc.2016.344

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  • DOI: https://doi.org/10.1038/onc.2016.344

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