Abstract

Thrombocytopenia is a major side effect of a new class of anticancer agents that target histone deacetylase (HDAC). Their mechanism is poorly understood. Here, we show that HDAC6 inhibition and genetic knockdown lead to a strong decrease in human proplatelet formation (PPF). Unexpectedly, HDAC6 inhibition-induced tubulin hyperacetylation has no effect on PPF. The PPF decrease induced by HDAC6 inhibition is related to cortactin (CTTN) hyperacetylation associated with actin disorganization inducing important changes in the distribution of megakaryocyte (MK) organelles. CTTN silencing in human MKs phenocopies HDAC6 inactivation and knockdown leads to a strong PPF defect. This is rescued by forced expression of a deacetylated CTTN mimetic. Unexpectedly, unlike human-derived MKs, HDAC6 and CTTN are shown to be dispensable for mouse PPF in vitro and platelet production in vivo. Our results highlight an unexpected function of HDAC6–CTTN axis as a positive regulator of human but not mouse MK maturation.

Details

Title
Critical role of the HDAC6–cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect
Author
Messaoudi, Kahia 1 ; Ashfaq, Ali 1 ; Ishaq, Rameez 1 ; Palazzo, Alberta 1 ; Sliwa, Dominika 2 ; Bluteau, Olivier 2 ; Souquère, Sylvie 3 ; Muller, Delphine 2 ; Diop, Khadija M 4 ; Rameau, Philippe 5 ; Lapierre, Valérie 6 ; Marolleau, Jean-Pierre 7 ; Patrick, Matthias 8 ; Godin, Isabelle 2 ; Pierron, Gérard 3 ; Thomas, Steven G 9   VIAFID ORCID Logo  ; Watson, Stephen P 9 ; Droin, Nathalie 10 ; Vainchenker, William 2 ; Plo, Isabelle 2 ; Raslova, Hana 2 ; Debili, Najet 2 

1  Institut National de la Santé et de la Recherche Médicale, UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer, Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, Villejuif, France; Paris7 Diderot University, Paris, France 
2  Institut National de la Santé et de la Recherche Médicale, UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer, Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, Villejuif, France 
3  CNRS-UMR-9196, Institut Gustave Roussy, Villejuif, France 
4  Genomic Platform, Institut Gustave Roussy, Villejuif, France 
5  Gustave Roussy, Integrated Biology Core Facility, Villejuif, France 
6  Gustave Roussy, Cell Therapy Unit, Villejuif, France 
7  Clinical Hematology and Cell Therapy Department, Amiens Hospital, UPJV University EA4666, Amiens, France 
8  Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland 
9  Institute of Cardiovascular Sciences, The Medical School, University of Birmingham, Edgbaston, Birmingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Midlands, UK 
10  Institut National de la Santé et de la Recherche Médicale, UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer, Villejuif, France; Paris-Saclay University, Villejuif, France; Gustave Roussy, Villejuif, France; Genomic Platform, Institut Gustave Roussy, Villejuif, France 
Pages
1-17
Publication year
2017
Publication date
Nov 2017
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-017-01690-2
ProQuest document ID
1968412798
Copyright
© 2017. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.