Critical role of the HDAC6–cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect

Kahia Messaoudi, Ashfaq Ali, Rameez Ishaq, Alberta Palazzo, Dominika Sliwa, Olivier Bluteau, Sylvie Souquère, Delphine Muller, Khadija M. Diop, Philippe Rameau, Valérie Lapierre, Jean-Pierre Marolleau, Patrick Matthias, Isabelle Godin, Gérard Pierron, Steven G. Thomas, Stephen P. Watson, Nathalie Droin, William Vainchenker, Isabelle Plo, Hana Raslova and Najet Debili ()
Additional contact information
Kahia Messaoudi: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Ashfaq Ali: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Rameez Ishaq: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Alberta Palazzo: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Dominika Sliwa: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Olivier Bluteau: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Sylvie Souquère: Institut Gustave Roussy
Delphine Muller: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Khadija M. Diop: Institut Gustave Roussy
Philippe Rameau: Integrated Biology Core Facility
Valérie Lapierre: Cell Therapy Unit
Jean-Pierre Marolleau: Amiens Hospital, UPJV University EA4666
Patrick Matthias: Friedrich Miescher Institute for Biomedical Research
Isabelle Godin: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Gérard Pierron: Institut Gustave Roussy
Steven G. Thomas: The Medical School, University of Birmingham, Edgbaston
Stephen P. Watson: The Medical School, University of Birmingham, Edgbaston
Nathalie Droin: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
William Vainchenker: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Isabelle Plo: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Hana Raslova: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer
Najet Debili: UMR 1170, Equipe labellisée par la Ligue Nationale contre le Cancer

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-01690-2

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