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

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 thi...

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Autores principales:	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
Formato:	article
Lenguaje:	EN
Publicado:	Wiley 2021
Materias:	acetylation apoptosis BAK mitochondria p53 replication stress Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/0b74c48fb69942fab1d217753fe500f2
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spelling	oai:doaj.org-article:0b74c48fb69942fab1d217753fe500f22021-12-02T10:31:06ZMechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells1878-02611574-789110.1002/1878-0261.13060https://doaj.org/article/0b74c48fb69942fab1d217753fe500f22021-12-01T00:00:00Zhttps://doi.org/10.1002/1878-0261.13060https://doaj.org/toc/1574-7891https://doaj.org/toc/1878-0261Late‐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.Christian MarxJürgen SonnemannMandy BeyerOliver D. K. MaddocksSergio LillaIrene HauzenbergerAndrea Piée‐StaffaKanstantsin SiniukSuneetha NunnaLisa Marx‐BlümelMartin WestermannTobias WagnerFelix B. MeyerRené ThierbachChristina S. MullinsSaid KdimatiMichael LinnebacherFrancesco NeriThorsten HeinzelZhao‐Qi WangOliver H. KrämerWileyarticleacetylationapoptosisBAKmitochondriap53replication stressNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENMolecular Oncology, Vol 15, Iss 12, Pp 3404-3429 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	acetylation apoptosis BAK mitochondria p53 replication stress Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	acetylation apoptosis BAK mitochondria p53 replication stress Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 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 Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells
description	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.
format	article
author	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
author_facet	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
author_sort	Christian Marx
title	Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells
title_short	Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells
title_full	Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells
title_fullStr	Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells
title_full_unstemmed	Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells
title_sort	mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells
publisher	Wiley
publishDate	2021
url	https://doaj.org/article/0b74c48fb69942fab1d217753fe500f2
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Mechanistic insights into p53‐regulated cytotoxicity of combined entinostat and irinotecan against colorectal cancer cells

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