TY - JOUR
T1 - HDAC6 inhibition upregulates CD20 levels and increases the efficacy of anti-CD20 monoclonal antibodies
AU - Laurenti, Luca
AU - Bobrowicz, Malgorzata
AU - Dwojak, Michal
AU - Pyrzynska, Beata
AU - Stachura, Joanna
AU - Muchowicz, Angelika
AU - Berthel, Elise
AU - Dalla-Venezia, Nicole
AU - Kozikowski, Mieszko
AU - Siernicka, Marta
AU - Miazek, Nina
AU - Zapala, Piotr
AU - Domagala, Antoni
AU - Bojarczuk, Kamil
AU - Malenda, Agata
AU - Barankiewicz, Joanna
AU - Graczyk-Jarzynka, Agnieszka
AU - Zagozdzon, Agnieszka
AU - Gabrysiak, Magdalena
AU - Diaz, Jean-Jacques
AU - Karp, Marta
AU - Lech-Maranda, Ewa
AU - Firczuk, Malgorzata
AU - Giannopoulos, Krzysztof
AU - Efremov, Dimitar G.
AU - Baatout, Dunja
AU - Frenzel, Lukas
AU - Malinowska, Agata
AU - Slabicki, Mikolaj
AU - Zenz, Thorsten
AU - Zerrouqi, Abdessamad
AU - Golab, Jakub
AU - Winiarska, Magdalena
PY - 2017
Y1 - 2017
N2 - 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.
AB - 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.
KW - Animals
KW - Antigens, CD20
KW - Antineoplastic Agents
KW - B-Lymphocytes
KW - Cell Line, Tumor
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Histone Deacetylase 6
KW - Histone Deacetylase Inhibitors
KW - Histone Deacetylases
KW - Humans
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Lymphoma, Non-Hodgkin
KW - Mice, Inbred BALB C
KW - Mice, SCID
KW - RNA, Messenger
KW - Rituximab
KW - Tumor Cells, Cultured
KW - Up-Regulation
KW - Animals
KW - Antigens, CD20
KW - Antineoplastic Agents
KW - B-Lymphocytes
KW - Cell Line, Tumor
KW - Female
KW - Gene Expression Regulation, Neoplastic
KW - Histone Deacetylase 6
KW - Histone Deacetylase Inhibitors
KW - Histone Deacetylases
KW - Humans
KW - Leukemia, Lymphocytic, Chronic, B-Cell
KW - Lymphoma, Non-Hodgkin
KW - Mice, Inbred BALB C
KW - Mice, SCID
KW - RNA, Messenger
KW - Rituximab
KW - Tumor Cells, Cultured
KW - Up-Regulation
UR - http://hdl.handle.net/10807/135398
U2 - 10.1182/blood-2016-08-736066
DO - 10.1182/blood-2016-08-736066
M3 - Article
VL - 130
SP - 1628
EP - 1638
JO - Blood
JF - Blood
SN - 0006-4971
ER -