title: Differential expression of histone deacetylase and acetyltransferase genes in gastric cancer and their modulation by trichostatin A.
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.
authors.affiliation: Disciplina de Genética, Departamento de Morfologia e Genética, Universidade Federal de São Paulo, Rua Botucatu, 740, São Paulo, 04023900, Brazil, fernandawis@yahoo.com.br.
authors.forename: Fernanda
authors.initials: F
authors.lastname: Wisnieski
authors.forename: Danielle Queiroz
authors.initials: DQ
authors.lastname: Calcagno
authors.forename: Mariana Ferreira
authors.initials: MF
authors.lastname: Leal
authors.forename: Elizabeth Suchi
authors.initials: ES
authors.lastname: Chen
authors.forename: Carolina Oliveira
authors.initials: CO
authors.lastname: Gigek
authors.forename: Leonardo Caires
authors.initials: LC
authors.lastname: Santos
authors.forename: Thaís Brilhante
authors.initials: TB
authors.lastname: Pontes
authors.forename: Lucas Trevizani
authors.initials: LT
authors.lastname: Rasmussen
authors.forename: Spencer Luiz Marques
authors.initials: SL
authors.lastname: Payão
authors.forename: Paulo Pimentel
authors.initials: PP
authors.lastname: Assumpção
authors.forename: Laércio Gomes
authors.initials: LG
authors.lastname: Lourenço
authors.forename: Sâmia
authors.initials: S
authors.lastname: Demachki
authors.forename: Ricardo
authors.initials: R
authors.lastname: Artigiani
authors.forename: Rommel Rodríguez
authors.initials: RR
authors.lastname: Burbano
authors.forename: Marília Cardoso
authors.initials: MC
authors.lastname: Smith
mesh_terms: D045744:Cell Line, Tumor; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000096:biosynthesis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D016259:Genes, myc / Q000235:genetics; D056284:Histone Deacetylase 1 / Q000096:biosynthesis / Q000235:genetics; D056464:Histone Deacetylase 2 / Q000096:biosynthesis / Q000235:genetics; D056572:Histone Deacetylase Inhibitors / Q000008:administration & dosage*; D006655:Histone Deacetylases / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage*; D012333:RNA, Messenger / Q000096:biosynthesis* / Q000235:genetics; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D015533:Transcriptional Activation / Q000187:drug effects; D050880:p300-CBP Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D056284:Histone Deacetylase 1; D056464:Histone Deacetylase 2; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases; D006877:Hydroxamic Acids; D012333:RNA, Messenger; D050880:p300-CBP Transcription Factors; D000099224:p300-CBP-Associated Factor; D000099186:Histone Deacetylase 3; C493956:CDKN1A protein, human; C012589:trichostatin A; C110550:HDAC1 protein, human; C533423:HDAC2 protein, human