Original Article

Citation: Cell Death and Disease (2015) 6, e1635; doi:10.1038/cddis.2014.594
Published online 12 February 2015

The transcriptional repressor HDAC7 promotes apoptosis and c-Myc downregulation in particular types of leukemia and lymphoma
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B Barneda-Zahonero1, O Collazo1,11, A Azagra1,11, I Fernández-Duran1, J Serra-Musach2, A B M M K Islam3, N Vega-García4, R Malatesta4, M Camós4, A Gómez5, L Román-González1, A Vidal6, N López-Bigas7,8, A Villanueva9, M Esteller5,8,10 and M Parra1

  1. 1Cellular Differentiation Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research institute (IDIBELL), Avenida Gran Via 199, 08908 L’Hospitalet, Barcelona, Spain
  2. 2Breast Cancer and Systems Biology Unit, Translational Research Laboratory, Catalan Institute of Oncology (ICO), Bellvitge Institute for Biomedical Research (IDIBELL), Avenida Gran Via s/n km 2.7, 08907 L’Hospitalet, Barcelona, Spain
  3. 3Department of Genetic Engineering & Biotechnology, University of Dhaka, Dhaka, Bangladesh
  4. 4Department of Hematology, Hospital Sant Joan de Déu, Barcelona, Spain
  5. 5Cancer Epigenetics Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research institute (IDIBELL), Avenida Gran Via 199, 08908 L’Hospitalet, Barcelona, Spain
  6. 6Department of Pathology, University Hospital of Bellvitge, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain
  7. 7Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, Dr Aiguader 88, 08003 Barcelona, Spain
  8. 8Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
  9. 9Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, Barcelona, Spain
  10. 10Department of Physiological Sciences II, School of Medicine, University of Barcelona, Barcelona, Spain

Correspondence: M Parra, Cellular Differentiation Group, Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), Avenida Gran Via 199, L’Hospitalet, 08908 Barcelona, Spain. Tel: +34 932 607133; Fax: +34 932 607219; E-mail: mparra@idibell.cat

11These authors contributed equally to this work.

Received 26 August 2014; Revised 16 December 2014; Accepted 18 December 2014

Edited by A Oberst

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Abstract

The generation of B cells is a complex process requiring several cellular transitions, including cell commitment and differentiation. Proper transcriptional control to establish the genetic programs characteristic of each cellular stage is essential for the correct development of B lymphocytes. Deregulation of these particular transcriptional programs may result in a block in B-cell maturation, contributing to the development of hematological malignancies such as leukemia and lymphoma. However, very little is currently known about the role of transcriptional repressors in normal and aberrant B lymphopoiesis. Here we report that histone deacetylase 7 (HDAC7) is underexpressed in pro-B acute lymphoblastic leukemia (pro-B-ALL) and Burkitt lymphoma. Ectopic expression of HDAC7 induces apoptosis, leads to the downregulation of c-Myc and inhibits the oncogenic potential of cells in vivo, in a xenograft model. Most significantly, we have observed low levels of HDAC7 expression in B-ALL patient samples, which is correlated with the increased levels of c-Myc. From a mechanistic angle, we show that ectopically expressed HDAC7 localizes to the nucleus and interacts with the transcription factor myocyte enhancer factor C (MEF2C) and the corepressors HDAC3 and SMRT. Accordingly, both the HDAC7–MEF2C interaction domain as well as its catalytic domain are involved in the reduced cell viability induced by HDAC7. We conclude that HDAC7 has a potent anti-oncogenic effect on specific B-cell malignancies, indicating that its deregulation may contribute to the pathogenesis of the disease.

Abbreviations:

HDAC7, histone deacetylase 7; B-ALL, B-cell acute lymphoblastic leukemia; MEF2C, myocyte enhancer factor C; HDIs, histone deacetylase inhibitors