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Annals of Hematology

, Volume 93, Issue 6, pp 983–993 | Cite as

Histone deacetylase inhibitor prevents cell growth in Burkitt’s lymphoma by regulating PI3K/Akt pathways and leads to upregulation of miR-143, miR-145, and miR-101

  • Ana Carolina dos Santos Ferreira
  • Marcela Cristina Robaina
  • Lídia Maria Magalhães de Rezende
  • Patricia Severino
  • Claudete Esteves KlumbEmail author
Original Article

Abstract

Burkitt lymphoma (BL) is an aggressive B-cell lymphoma more common in children comprising one third of pediatric non-Hodgkin lymphoma cases. The recent discovery in BL pathogenesis highlighted the activation of PI3K pathway in cooperation with Myc in the development of BL. In this study, we demonstrated that PI3K/Akt pathway is a target to histone deacetylase inhibitor (HDACi) in BL cells. The combination of HDACi (sodium butyrate, NaB) and chemotherapy (VP-16) inhibited 51 % of the proliferation and enhanced the blockage of the cell cycle progression at G2/M with a concurrent decrease in the S phase. Microarray profiling showed a synergistic action of NaB/VP-16 combination through the differential regulation of 1,413 genes. Comparing VP-16 treatment with the NaB/VP-16 combination, 318 genes were deregulated: 250 genes were downregulated, and 68 were upregulated when compared with untreated cells. Among these genes, six (CDKN1A, CCND1, FAS, CHEK2, MDM4, and SESN2) belong to the p53-signaling pathway. The activation of this signaling pathway is usually induced by stress signals and ultimately leads to cell cycle arrest. Besides, the inhibition of the cell growth was related to reduced Akt phosphorylation, and decrease of c-Myc protein expression by about 60 % (p ≤ 0.005). Moreover, HDACi enhanced miR-101, miR-143, and miR-145 levels in BL cell line, which were inversely associated with the levels of miR-101, miR-143, and miR-145 found to be extremely downregulated in the sample of BL patients. We highlight the fact that effective combinations of HDACis with other target drugs could improve BL therapy in the future.

Keywords

Burkitt’s lymphoma HDACi Cell growth PI3K miRNA 

Notes

Acknowledgments

This work was supported by grants from INCT para Controle do Câncer: CNPq 573806/2008-0/FAPERJ E26/170.026/2008 and FAPERJ E-26/111330/2011.

Conflict of interest

The authors have no financial gains to disclose.

Supplementary material

277_2014_2021_MOESM1_ESM.doc (561 kb)
Supplementary File 1 Differentially expressed genes between VP-16 treated cells and controls. Reported genes presented at least a 1.5-fold change between the two cell treatment (FDR corrected p value) (DOC 561 kb)
277_2014_2021_MOESM2_ESM.doc (768 kb)
Supplementary File 2 Differentially expressed genes between NaB treated cells and controls. Reported genes presented at least a 1.5-fold change between the two cell treatments (FDR corrected p value) (DOC 767 kb)
277_2014_2021_MOESM3_ESM.doc (1.1 mb)
Supplementary File 3 Differentially expressed genes between VP16/NaB treated cells and controls. Reported genes presented at least a 1.5-fold change between the two cell treatments (FDR corrected p value) (DOC 1087 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Ana Carolina dos Santos Ferreira
    • 1
  • Marcela Cristina Robaina
    • 1
  • Lídia Maria Magalhães de Rezende
    • 2
  • Patricia Severino
    • 3
  • Claudete Esteves Klumb
    • 1
    • 4
    Email author
  1. 1.Programa de Pesquisa em Hemato-Oncologia Molecular, Coordenação Geral Técnico-CientíficaInstituto Nacional de Câncer-INCARio de JaneiroBrazil
  2. 2.Divisão de PatologiaInstituto Nacional de Câncer-INCARio de JaneiroBrazil
  3. 3.Instituto Israelita de Ensino e Pesquisa Albert EinsteinHospital Israelita Albert EinsteinSão PauloBrazil
  4. 4.Laboratório de Hemato-Oncologia Celular e Molecular; Programa de Pesquisa em Hemato-Oncologia Molecular; CGTCInstituto Nacional de CâncerRio de JaneiroBrazil

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