Critical role of the HDAC6-cortactin axis in human megakaryocytes 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 Thomas, Steve Watson, Nathalie Droin, William Vainchenker, Isabelle PloHana Raslova , Najet Debili

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Abstract

Thrombocytopenia is a major side-effect of a new class of anticancer agent that targets histone deacetylase (HDAC). Their mechanism is poorly understood. Here we show that HDAC6 inhibition and genetic knockdown (KD) 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-MK 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 MK, 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.
Original languageEnglish
Article number1786
JournalNature Communications
Volume8
DOIs
Publication statusPublished - 27 Nov 2017

Keywords

  • acetylation
  • cytoskeleton
  • platelets

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