title: Inhibitor of DNA binding 4 functions as a tumor suppressor and is targetable by 5-aza-2'-deoxycytosine with potential therapeutic significance in Burkitt's lymphoma.
abstract: Epigenetic gene silencing due to promoter methylation is observed in human neoplasia, including lymphoma and certain cancer types. One important target for gene methylation analysis in non-Hodgkin lymphoma (NHL) is inhibitor of DNA binding 4 (ID4). The present study aimed to investigate the gene methylation status of ID4, the expression of ID4 protein and the effect of demethylating agent 5-aza-2'-deoxycytosine (CdR) in the Raji human Burkitt's lymphoma cell line in vitro. Following assessment of the inhibition of Raji cell growth by various concentrations of CdR, the effects of CdR on the expression of ID4 protein were assessed using the immunocytochemical streptavidin-peroxidase method and semi-quantitative analysis, while apoptosis and cell cycle were determined by flow cytometry. The ID4 gene methylation status of Raji cells was tested using methylation-specific polymerase chain reaction analysis. ID4 was methylated and its protein expression was low in the control group, while ID4 was partly or completely demethylated and its protein expression was upregulated in Raji cells treated with CdR. In addition, CdR induced apoptosis and cell cycle arrest in Raji cells in a dose- and time-dependent manner. These results demonstrated that ID4 is hypermethylated and its protein expression is low in Burkitt's lymphoma cells, while CdR reversed the abnormal DNA methylation and induced re-expression of ID4 protein. Hypermethylation of ID4 promotes the proliferation of Burkitt's lymphoma cells; ID4 may function as a tumor suppressor and can be targeted with demethylating compounds such as CdR for the treatment of Burkitt's lymphoma.
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors.forename: Xian-Zheng
authors.initials: XZ
authors.lastname: Gao
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors.forename: Wu-Gan
authors.initials: WG
authors.lastname: Zhao
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors.forename: Guan-Nan
authors.initials: GN
authors.lastname: Wang
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors.forename: Mei-Ying
authors.initials: MY
authors.lastname: Cui
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors.forename: Yang-Rui
authors.initials: YR
authors.lastname: Zhang
authors.affiliation: Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China.
authors.forename: Wen-Cai
authors.initials: WC
authors.lastname: Li
mesh_terms: D017209:Apoptosis / Q000235:genetics; D001374:Azacitidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000473:pathology; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D000077209:Decitabine; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020868:Gene Silencing; D016147:Genes, Tumor Suppressor; D006801:Humans; D051796:Inhibitor of Differentiation Proteins / Q000096:biosynthesis / Q000235:genetics*; D011401:Promoter Regions, Genetic
chemical_list: C490128:ID4 protein, human; D051796:Inhibitor of Differentiation Proteins; D000077209:Decitabine; D001374:Azacitidine