Stojanovic, N. and Hassan, Z. and Wirth, M. and Wenzel, P. and Beyer, M. and Schaefer, C. and Brand, P. and Kroemer, A. and Stauber, R. H. and Schmid, R. M. and Arlt, A. and Sellmer, A. and Mahboobi, S. and Rad, R. and Reichert, M. and Saur, D. and Kraemer, O. H. and Schneider, G. (2017) HDAC1 and HDAC2 integrate the expression of p53 mutants in pancreatic cancer. ONCOGENE, 36 (13). pp. 1804-1815. ISSN 0950-9232, 1476-5594
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | HISTONE DEACETYLASE INHIBITORS; NF-KAPPA-B; TUMOR-SUPPRESSOR GENE; MULTIPLE-MYELOMA; TRICHOSTATIN-A; BREAST-CANCER; MOUSE MODELS; CELL-LINES; STEM-CELLS; IN-VIVO; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry I (Prof. Elz) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:00 |
| Last Modified: | 25 Feb 2019 10:58 |
| URI: | https://pred.uni-regensburg.de/id/eprint/191 |
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