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Tumor Biology

, Volume 35, Issue 7, pp 6373–6381 | Cite as

Differential expression of histone deacetylase and acetyltransferase genes in gastric cancer and their modulation by trichostatin A

  • Fernanda WisnieskiEmail author
  • Danielle Queiroz Calcagno
  • Mariana Ferreira Leal
  • Elizabeth Suchi Chen
  • Carolina Oliveira Gigek
  • Leonardo Caires Santos
  • Thaís Brilhante Pontes
  • Lucas Trevizani Rasmussen
  • Spencer Luiz Marques Payão
  • Paulo Pimentel Assumpção
  • Laércio Gomes Lourenço
  • Sâmia Demachki
  • Ricardo Artigiani
  • Rommel Rodríguez Burbano
  • Marília Cardoso Smith
Research Article

Abstract

Gastric cancer is still the second leading cause of cancer-related death worldwide, even though its incidence and mortality have declined over the recent few decades. Epigenetic control using histone deacetylase inhibitors, such as trichostatin A (TSA), is a promising cancer therapy. This study aimed to assess the messenger RNA (mRNA) levels of three histone deacetylases (HDAC1, HDAC2, and HDAC3), two histone acetyltransferases (GCN5 and PCAF), and two possible targets of these histone modifiers (MYC and CDKN1A) in 50 matched pairs of gastric tumors and corresponding adjacent nontumors samples from patients with gastric adenocarcinoma, as well as their correlations and their possible associations with clinicopathological features. Additionally, we evaluated whether these genes are sensitive to TSA in gastric cancer cell lines. Our results demonstrated downregulation of HDAC1, PCAF, and CDKN1A in gastric tumors compared with adjacent nontumors (P < 0.05). On the other hand, upregulation of HDAC2, GCN5, and MYC was observed in gastric tumors compared with adjacent nontumors (P < 0.05). The mRNA level of MYC was correlated to HDAC3 and GCN5 (P < 0.05), whereas CDKN1A was correlated to HDAC1 and GCN5 (P < 0.05 and P < 0.01, respectively). In addition, the reduced expression of PCAF was associated with intestinal-type gastric cancer (P = 0.03) and TNM stages I/II (P = 0.01). The increased expression of GCN5 was associated with advanced stage gastric cancer (P = 0.02) and tumor invasion (P = 0.03). The gastric cell lines treated with TSA showed different patterns of histone deacetylase and acetyltransferase mRNA expression, downregulation of MYC, and upregulation of CDKN1A. Our findings suggest that alteration of histone modifier genes play an important role in gastric carcinogenesis, contributing to MYC and CDKN1A deregulation. In addition, all genes studied here are modulated by TSA, although this modulation appears to be dependent of the genetic background of the cell line.

Keywords

Gastric cancer Acetylation Histone acetyltransferase Histone deacetylase Gene expression 

Abbreviations

GC

Gastric cancer

HATs

Histone acetyltransferases

HDACs

Histone deacetylases

MTT

(3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, RQ, Relative quantification

RT-qPCR

Reverse transcription quantitative polymerase chain reaction

TNM

Tumor–node–metastasis

TSA

Trichostatin A

Notes

Acknowledgments

This paper was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP; to MACS, FW, DQC, MFL, and TBP), Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq; to MCS and RRB), and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES; to COG).

Conflicts of interest

None.

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Fernanda Wisnieski
    • 1
    Email author
  • Danielle Queiroz Calcagno
    • 1
    • 5
  • Mariana Ferreira Leal
    • 1
    • 2
  • Elizabeth Suchi Chen
    • 1
  • Carolina Oliveira Gigek
    • 1
  • Leonardo Caires Santos
    • 1
  • Thaís Brilhante Pontes
    • 1
  • Lucas Trevizani Rasmussen
    • 3
  • Spencer Luiz Marques Payão
    • 4
  • Paulo Pimentel Assumpção
    • 5
  • Laércio Gomes Lourenço
    • 6
  • Sâmia Demachki
    • 5
  • Ricardo Artigiani
    • 7
  • Rommel Rodríguez Burbano
    • 8
  • Marília Cardoso Smith
    • 1
  1. 1.Disciplina de Genética, Departamento de Morfologia e GenéticaUniversidade Federal de São PauloSão PauloBrazil
  2. 2.Departamento de Ortopedia e TraumatologiaUniversidade Federal de São PauloSão PauloBrazil
  3. 3.Pro-Reitoria de Pesquisa e Pós-GraduaçãoUniversidade do Sagrado CoraçãoBauruBrazil
  4. 4.Departamento de Genética e Biologia Molecular, HemocentroFaculdade de Medicina de MaríliaMaríliaBrazil
  5. 5.Núcleo de Pesquisa em Oncologia, Hospital João de Barros BarretoUniversidade Federal do ParáBelémBrazil
  6. 6.Disciplina de Gastroenterologia Cirúrgica, Departamento de CirurgiaUniversidade Federal de São PauloSão PauloBrazil
  7. 7.Departamento de PatologiaUniversidade Federal de São PauloSão PauloBrazil
  8. 8.Laboratório de Citogenética Humana, Instituto de Ciências BiológicasUniversidade Federal do ParáBelémBrazil

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