Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells

Marx, C. et al. (2021) Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells. Molecular Oncology, 15(12), pp. 3404-3429. (doi: 10.1002/1878-0261.13060) (PMID:34258881) (PMCID:PMC8637561)

Abstract

Late‐stage colorectal cancer (CRC) is still a clinically challenging problem. The activity of the tumor suppressor p53 is regulated via post‐translational modifications (PTMs). While the relevance of p53 C‐terminal acetylation for transcriptional regulation is well defined, it is unknown whether this PTM controls mitochondrially mediated apoptosis directly. We used wild‐type p53 or p53‐negative human CRC cells, cells with acetylation‐defective p53, transformation assays, CRC organoids, and xenograft mouse models to assess how p53 acetylation determines cellular stress responses. The topoisomerase‐1 inhibitor irinotecan induces acetylation of several lysine residues within p53. Inhibition of histone deacetylases (HDACs) with the class I HDAC inhibitor entinostat synergistically triggers mitochondrial damage and apoptosis in irinotecan‐treated p53‐positive CRC cells. This specifically relies on the C‐terminal acetylation of p53 by CREB‐binding protein/p300 and the presence of C‐terminally acetylated p53 in complex with the proapoptotic BCL2 antagonist/killer protein. This control of C‐terminal acetylation by HDACs can mechanistically explain why combinations of irinotecan and entinostat represent clinically tractable agents for the therapy of p53‐proficient CRC.

• Item Type: Articles
• Additional Information: This work includes parts of the PhD theses of CM and IH. CM was funded by the DFG research training group RTG1715 SP13 (to OHK), the Boehringer Ingelheim fonds (BIF) (to CM), and the Richard-Winter-Stiftung (to CM). LM-B was funded by the Graduate Academy (GA) of the Friedrich-Schiller-University (FSU) Jena. Additional support to OHK is from the Deutsche Forschungsgemeinschaft (#KR2291/8-1/9-1/12-1, DFG-project number 393547839—SFB 1361, sub-project 11), the Wilhelm Sander Stiftung (2019.086.1), and the Brigitte und Dr. Konstanze Wegener Stiftung (#65). Open Access funding enabled and organized by Projekt DEAL.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Lilla, Dr Sergio and Maddocks, Professor Oliver
• Authors: Marx, C., Sonnemann, J., Beyer, M., Maddocks, O. D.K., Lilla, S., Hauzenberger, I., Piée‐Staffa, A., Siniuk, K., Nunna, S., Marx‐Blümel, L., Westermann, M., Wagner, T., Meyer, F. B., Thierbach, R., Mullins, C. S., Kdimati, S., Linnebacher, M., Neri, F., Heinzel, T., Wang, Z.‐Q., and Krämer, O. H.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Oncology
• Publisher: Wiley
• ISSN: 1574-7891
• ISSN (Online): 1878-0261
• Published Online: 14 July 2021
• Copyright Holders: Copyright © 2021 The Authors
• First Published: First published in Molecular Oncology 15(12): 3404-3429
• Publisher Policy: Reproduced under a Creative Commons Licence