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

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.

• Authors: Christian Marx, Jürgen Sonnemann, Mandy Beyer, Oliver D K Maddocks, Sergio Lilla, Irene Hauzenberger, Andrea Piée-Staffa, Kanstantsin Siniuk, Suneetha Nunna, Lisa Marx-Blümel, Martin Westermann, Tobias Wagner, Felix B Meyer, René Thierbach, Christina S Mullins, Said Kdimati, Michael Linnebacher, Francesco Neri, Thorsten Heinzel, Zhao-Qi Wang, Oliver H Krämer
• Journal: Molecular oncology (Mol Oncol) Vol. 15 Issue 12 Pg. 3404-3429 (12 2021) ISSN: 1878-0261 [Electronic] United States
• PMID: 34258881 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.

Chemical References

• Benzamides
• Pyridines
• Tumor Suppressor Protein p53
• entinostat
• Irinotecan

Topics

• Acetylation
• Animals
• Apoptosis
• Benzamides
• Colorectal Neoplasms (drug therapy)
• Humans
• Irinotecan (pharmacology)
• Mice
• Pyridines
• Tumor Suppressor Protein p53 (metabolism)