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HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies

Object's details: HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies

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Provider:Repozytorium Instytutu Biochemii i Biofizyki Polskiej Akademii Nauk

Description

Title:
HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies
Creator:
Bobrowicz, Malgorzata;
Dwojak, Michal;
Pyrzynska, Beata;
Stachura, Joanna;
Muchowicz, Angelika;
Berthel, Elise;
Dalla-Venezia, Nicole;
Kozikowski, Mieszko;
Siernicka, Marta;
Miazek, Nina;
Zapala, Piotr;
Domagala, Antoni;
Bojarczuk, Kamil;
Malenda, Agata;
Barankiewicz, Joanna;
Graczyk-Jarzynka, Agnieszka;
Zagozdzon, Agnieszka;
Gabrysiak, Magdalena;
Diaz, Jean-Jacques;
Karp, Marta;
Lech-Maranda, Ewa;
Firczuk, Małgorzata;
Giannopoulos, Krzysztof;
Efremov, Dimitar G.;
Laurenti, Luca;
Baatout, Dunja;
Frenzel, Lukas;
Malinowska, Agata;
Slabicki, Mikolaj;
Zenz, Thorsten;
Zerrouqi, Abdessamad;
Golab, Jakub;
Winiarska, Magdalena
Description:
Downregulation of CD20, a molecular target for monoclonal antibodies (mAbs), is a clinical problem leading to decreased efficacy of anti-CD20-based therapeutic regimens. The epigenetic modulation of CD20 coding gene (MS4A1) has been proposed as a mechanism for the reduced therapeutic efficacy of anti-CD20 antibodies and confirmed with nonselective histone deacetylase inhibitors (HDACis). Because the use of pan-HDACis is associated with substantial adverse effects, the identification of particular HDAC isoforms involved in CD20 regulation seems to be of paramount importance. In this study, we demonstrate for the first time the role of HDAC6 in the regulation of CD20 levels. We show that inhibition of HDAC6 activity significantly increases CD20 levels in established B-cell tumor cell lines and primary malignant cells. Using pharmacologic and genetic approaches, we confirm that HDAC6 inhibition augments in vitro efficacy of anti-CD20 mAbs and improves survival of mice treated with rituximab. Mechanistically, we demonstrate that HDAC6 influences synthesis of CD20 protein independently of the regulation of MS4A1 transcription. We further demonstrate that translation of CD20 mRNA is significantly enhanced after HDAC6 inhibition, as shown by the increase of CD20 mRNA within the polysomal fraction, indicating a new role of HDAC6 in the posttranscriptional mechanism of CD20 regulation. Collectively, our findings suggest HDAC6 inhibition is a rational therapeutic strategy to be implemented in combination therapies with anti-CD20 monoclonal antibodies and open up novel avenues for the clinical use of HDAC6 inhibitors.
Object availability:
free access
Date:
2017
Type:
Article;
NonPeerReviewed
Publisher:
Am Soc Hematology
Relation: http://eprints.ibb.waw.pl/1412
Subject:
QH301 Biology
Identifier:
Bobrowicz, Malgorzata and Dwojak, Michal and Pyrzynska, Beata and Stachura, Joanna and Muchowicz, Angelika and Berthel, Elise and Dalla-Venezia, Nicole and Kozikowski, Mieszko and Siernicka, Marta and Miazek, Nina and Zapala, Piotr and Domagala, Antoni and Bojarczuk, Kamil and Malenda, Agata and Barankiewicz, Joanna and Graczyk-Jarzynka, Agnieszka and Zagozdzon, Agnieszka and Gabrysiak, Magdalena and Diaz, Jean-Jacques and Karp, Marta and Lech-Maranda, Ewa and Firczuk, Małgorzata and Giannopoulos, Krzysztof and Efremov, Dimitar G. and Laurenti, Luca and Baatout, Dunja and Frenzel, Lukas and Malinowska, Agata and Slabicki, Mikolaj and Zenz, Thorsten and Zerrouqi, Abdessamad and Golab, Jakub and Winiarska, Magdalena (2017) HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies. Blood, 130 (14). pp. 1628-1638.
Data provider:
Repozytorium Instytutu Biochemii i Biofizyki Polskiej Akademii Nauk

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