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HDAC6 regulates human erythroid differentiation through modulation of JAK2 signalling

Among histone deacetylases, HDAC6 is unusual in its cytoplasmic localization. Its inhibition leads to hyperacetylation of non‐histone proteins, inhibiting cell cycle, proliferation and apoptosis. Ricolinostat (ACY‐1215) is a selective inhibitor of the histone deacetylase HDAC6 with proven efficacy i...

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Autores principales: Vong, Pascal, Messaoudi, Kahia, Jankovsky, Nicolas, Gomilla, Cathy, Demont, Yohann, Caulier, Alexis, Jedraszak, Guillaume, Demagny, Julien, Djordjevic, Stefan, Boyer, Thomas, Marolleau, Jean Pierre, Rochette, Jacques, Ouled‐Haddou, Hakim, Garçon, Loïc
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843532/
https://www.ncbi.nlm.nih.gov/pubmed/36578217
http://dx.doi.org/10.1111/jcmm.17559
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author Vong, Pascal
Messaoudi, Kahia
Jankovsky, Nicolas
Gomilla, Cathy
Demont, Yohann
Caulier, Alexis
Jedraszak, Guillaume
Demagny, Julien
Djordjevic, Stefan
Boyer, Thomas
Marolleau, Jean Pierre
Rochette, Jacques
Ouled‐Haddou, Hakim
Garçon, Loïc
author_facet Vong, Pascal
Messaoudi, Kahia
Jankovsky, Nicolas
Gomilla, Cathy
Demont, Yohann
Caulier, Alexis
Jedraszak, Guillaume
Demagny, Julien
Djordjevic, Stefan
Boyer, Thomas
Marolleau, Jean Pierre
Rochette, Jacques
Ouled‐Haddou, Hakim
Garçon, Loïc
author_sort Vong, Pascal
collection PubMed
description Among histone deacetylases, HDAC6 is unusual in its cytoplasmic localization. Its inhibition leads to hyperacetylation of non‐histone proteins, inhibiting cell cycle, proliferation and apoptosis. Ricolinostat (ACY‐1215) is a selective inhibitor of the histone deacetylase HDAC6 with proven efficacy in the treatment of malignant diseases, but anaemia is one of the most frequent side effects. We investigated here the underlying mechanisms of this erythroid toxicity. We first confirmed that HDAC6 was strongly expressed at both RNA and protein levels in CD34(+)‐cells‐derived erythroid progenitors. ACY‐1215 exposure on CD34(+)‐cells driven in vitro towards the erythroid lineage led to a decreased cell count, an increased apoptotic rate and a delayed erythroid differentiation with accumulation of weakly hemoglobinized immature erythroblasts. This was accompanied by drastic changes in the transcriptomic profile of primary cells as shown by RNAseq. In erythroid cells, ACY‐1215 and shRNA‐mediated HDAC6 knockdown inhibited the EPO‐dependent JAK2 phosphorylation. Using acetylome, we identified 14‐3‐3ζ, known to interact directly with the JAK2 negative regulator LNK, as a potential HDAC6 target in erythroid cells. We confirmed that 14‐3‐3ζ was hyperacetylated after ACY‐1215 exposure, which decreased the 14‐3‐3ζ/LNK interaction while increased LNK ability to interact with JAK2. Thus, in addition to its previously described role in the enucleation of mouse fetal liver erythroblasts, we identified here a new mechanism of HDAC6‐dependent control of erythropoiesis through 14‐3‐3ζ acetylation level, LNK availability and finally JAK2 activation in response to EPO, which is crucial downstream of EPO‐R activation for human erythroid cell survival, proliferation and differentiation.
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spelling pubmed-98435322023-01-23 HDAC6 regulates human erythroid differentiation through modulation of JAK2 signalling Vong, Pascal Messaoudi, Kahia Jankovsky, Nicolas Gomilla, Cathy Demont, Yohann Caulier, Alexis Jedraszak, Guillaume Demagny, Julien Djordjevic, Stefan Boyer, Thomas Marolleau, Jean Pierre Rochette, Jacques Ouled‐Haddou, Hakim Garçon, Loïc J Cell Mol Med Original Articles Among histone deacetylases, HDAC6 is unusual in its cytoplasmic localization. Its inhibition leads to hyperacetylation of non‐histone proteins, inhibiting cell cycle, proliferation and apoptosis. Ricolinostat (ACY‐1215) is a selective inhibitor of the histone deacetylase HDAC6 with proven efficacy in the treatment of malignant diseases, but anaemia is one of the most frequent side effects. We investigated here the underlying mechanisms of this erythroid toxicity. We first confirmed that HDAC6 was strongly expressed at both RNA and protein levels in CD34(+)‐cells‐derived erythroid progenitors. ACY‐1215 exposure on CD34(+)‐cells driven in vitro towards the erythroid lineage led to a decreased cell count, an increased apoptotic rate and a delayed erythroid differentiation with accumulation of weakly hemoglobinized immature erythroblasts. This was accompanied by drastic changes in the transcriptomic profile of primary cells as shown by RNAseq. In erythroid cells, ACY‐1215 and shRNA‐mediated HDAC6 knockdown inhibited the EPO‐dependent JAK2 phosphorylation. Using acetylome, we identified 14‐3‐3ζ, known to interact directly with the JAK2 negative regulator LNK, as a potential HDAC6 target in erythroid cells. We confirmed that 14‐3‐3ζ was hyperacetylated after ACY‐1215 exposure, which decreased the 14‐3‐3ζ/LNK interaction while increased LNK ability to interact with JAK2. Thus, in addition to its previously described role in the enucleation of mouse fetal liver erythroblasts, we identified here a new mechanism of HDAC6‐dependent control of erythropoiesis through 14‐3‐3ζ acetylation level, LNK availability and finally JAK2 activation in response to EPO, which is crucial downstream of EPO‐R activation for human erythroid cell survival, proliferation and differentiation. John Wiley and Sons Inc. 2022-12-28 /pmc/articles/PMC9843532/ /pubmed/36578217 http://dx.doi.org/10.1111/jcmm.17559 Text en © 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Vong, Pascal
Messaoudi, Kahia
Jankovsky, Nicolas
Gomilla, Cathy
Demont, Yohann
Caulier, Alexis
Jedraszak, Guillaume
Demagny, Julien
Djordjevic, Stefan
Boyer, Thomas
Marolleau, Jean Pierre
Rochette, Jacques
Ouled‐Haddou, Hakim
Garçon, Loïc
HDAC6 regulates human erythroid differentiation through modulation of JAK2 signalling
title HDAC6 regulates human erythroid differentiation through modulation of JAK2 signalling
title_full HDAC6 regulates human erythroid differentiation through modulation of JAK2 signalling
title_fullStr HDAC6 regulates human erythroid differentiation through modulation of JAK2 signalling
title_full_unstemmed HDAC6 regulates human erythroid differentiation through modulation of JAK2 signalling
title_short HDAC6 regulates human erythroid differentiation through modulation of JAK2 signalling
title_sort hdac6 regulates human erythroid differentiation through modulation of jak2 signalling
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9843532/
https://www.ncbi.nlm.nih.gov/pubmed/36578217
http://dx.doi.org/10.1111/jcmm.17559
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