Oncotarget

Research Papers:

Impaired expression of DICER and some microRNAs in HBZ expressing cells from acute adult T-cell leukemia patients

Hélène Gazon, Gildas Belrose, Marie Terol, Jean-Come Meniane, Jean-Michel Mesnard, Raymond Césaire and Jean-Marie Peloponese Jr _

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Oncotarget. 2016; 7:30258-30275. https://doi.org/10.18632/oncotarget.7162

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Abstract

Hélène Gazon1,2, Gildas Belrose2, Marie Terol1,2, Jean-Come Meniane3, Jean-Michel Mesnard1, Raymond Césaire2, Jean-Marie Peloponese Jr1

1CPBS, CNRS UMR 5236, Université Montpellier 1, Montpellier, France

2Laboratoire de Virologie-Immunologie JE2503, Centre Hospitalier et Universitaire de Martinique, Fort de France, Martinique

3Service hématologie clinique, Centre Hospitalier et Universitaire de Martinique, Fort de France, Martinique

Correspondence to:

Jean-Marie Peloponese, email: [email protected]

Keywords: Dicer, miRNAs, AP-1, JunD, HBZ

Received: September 16, 2015    Accepted: January 20, 2016    Published: February 03, 2016

ABSTRACT

Global dysregulation of microRNAs (miRNAs), a class of non-coding RNAs that regulate genes expression, is a common feature of human tumors. Profiling of cellular miRNAs on Adult T cell Leukemia (ATL) cells by Yamagishi et al. showed a strong decrease in expression for 96.7% of cellular miRNAs in ATL cells. However, the mechanisms that regulate the expression of miRNAs in ATL cells are still largely unknown. In this study, we compared the expression of 12 miRs previously described for being overexpress by Tax and the expression of several key components of the miRNAs biogenesis pathways in different HBZ expressing cell lines as well as in primary CD4 (+) cells from acute ATL patients. We showed that the expression of miRNAs and Dicer1 were downregulated in cells lines expressing HBZ as well as in fresh CD4 (+) cells from acute ATL patients. Using qRT-PCR, western blotting analysis and Chromatin Immunoprecipitation, we showed that dicer transcription was regulated by c-Jun and JunD, two AP-1 transcription factors. We also demonstrated that HBZ affects the expression of Dicer by removing JunD from the proximal promoter. Furthermore, we showed that at therapeutic concentration of 1mM, Valproate (VPA) an HDAC inhibitors often used in cancer treatment, rescue Dicer expression and miRNAs maturation. These results might offer a rationale for clinical studies of new combined therapy in an effort to improve the outcome of patients with acute ATL.


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