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

Malgorzata Bobrowicz, Michal Dwojak, Beata Pyrzynska, Joanna Stachura, Angelika Muchowicz, Elise Berthel, Nicole Dalla-Venezia, Mieszko Kozikowski, Marta Siernicka, Nina Miazek, Piotr Zapala, Antoni Domagala, Kamil Bojarczuk, Agata Malenda, Joanna Barankiewicz, Agnieszka Graczyk-Jarzynka, Agnieszka Zagozdzon, Magdalena Gabrysiak, Jean-Jacques Diaz, Marta Karp, Ewa Lech-Maranda, Malgorzata Firczuk, Krzysztof Giannopoulos, Dimitar G. Efremov, Luca Laurenti, Dunja Baatout, Lukas Frenzel, Agata Malinowska, Mikolaj Slabicki, Thorsten Zenz, Abdessamad Zerrouqi, Jakub Golab and Magdalena Winiarska

Key Points

  • HDAC6 inhibition represents a novel strategy to improve the efficacy of anti-CD20 mAbs.

  • HDAC6 inhibition increases CD20 levels by enhancing CD20 protein synthesis without affecting the gene expression.

Abstract

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.

  • Submitted August 25, 2016.
  • Accepted August 7, 2017.
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