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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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.].
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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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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