Advances in Brief Analysis of Gene Induction in Human Fibroblasts and Bladder Cancer Cells Exposed to the Methylation Inhibitor 5-Aza-2-deoxycytidine 1

Hypermethylation of the promoters of cancer-related genes is often associated with their inactivation during tumorigenesis. Several preclinical and clinical trials have been developed to use DNA methylation inhibitors, such as 5-aza-2 -deoxycytidine (5-Aza-CdR) in attempts to reactivate silenced genes in human cancers. We used high-density oligonucleotide gene expression microarrays to examine the effects of 5-AzaCdR treatment on human fibroblast cells (LD419) and a human bladder tumor cell line (T24). Data obtained 8 days after recovery from 5-AzaCdR treatment showed that more genes were induced in tumorigenic cells (61 genes induced; > 4-fold) than nontumorigenic cells (34 genes induced; > 4-fold). Approximately 60% of induced genes did not have CpG islands within their 5 regions, suggesting that some genes activated by 5-AzaCdR may not result from the direct inhibition of promoter methylation. Interestingly, a high percentage of genes activated in both cell types belonged to the IFN signaling pathway, confirming data from other tumor cell types.

[1]  Peter A. Jones,et al.  The Role of DNA Methylation in Mammalian Epigenetics , 2001, Science.

[2]  C Eng,et al.  Excessive CpG island hypermethylation in cancer cell lines versus primary human malignancies. , 2001, Human molecular genetics.

[3]  J. Herman,et al.  A gene hypermethylation profile of human cancer. , 2001, Cancer research.

[4]  J. Herman,et al.  Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer. , 2001, Human molecular genetics.

[5]  H. Nishimatsu,et al.  Silencing of the caspase‐1 gene occurs in murine and human renal cancer cells and causes solid tumor growth in vivo , 2001, International journal of cancer.

[6]  R. Ho,et al.  Resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in neuroblastoma cells correlates with a loss of caspase-8 expression. , 2001, Cancer research.

[7]  W. Gerald,et al.  Inactivation of the apoptosis effector Apaf-1 in malignant melanoma , 2001, Nature.

[8]  G. Liang,et al.  PAX6 methylation and ectopic expression in human tumor cells , 2000, International journal of cancer.

[9]  M. Lübbert,et al.  Low-dose 5-aza-2'-deoxycytidine, a DNA hypomethylating agent, for the treatment of high-risk myelodysplastic syndrome: a multicenter phase II study in elderly patients. , 2000, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  H. Albertsen,et al.  Inhibition of DNA methyltransferase stimulates the expression of signal transducer and activator of transcription 1, 2, and 3 genes in colon tumor cells. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[11]  Peter A. Jones,et al.  Roles of Cell Division and Gene Transcription in the Methylation of CpG Islands , 1999, Molecular and Cellular Biology.

[12]  Peter A. Jones,et al.  Cancer-epigenetics comes of age , 1999, Nature Genetics.

[13]  D. Botstein,et al.  Cluster analysis and display of genome-wide expression patterns. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[14]  T. Gingeras,et al.  Cellular gene expression altered by human cytomegalovirus: global monitoring with oligonucleotide arrays. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[15]  C. Walsh,et al.  Transcription of IAP endogenous retroviruses is constrained by cytosine methylation , 1998, Nature Genetics.

[16]  G. Stark,et al.  How cells respond to interferons. , 1998, Annual review of biochemistry.

[17]  Yao-Tseng Chen,et al.  Expression of SSX genes in human tumors , 1998, International journal of cancer.

[18]  M. Linsenmeyer,et al.  Asymmetric Methylation in the Hypermethylated CpG Promoter Region of the Human L1 Retrotransposon* , 1997, The Journal of Biological Chemistry.

[19]  P. Bruggen,et al.  Human tumor antigens recognized by T lymphocytes , 1996, The Journal of experimental medicine.

[20]  J. Stevens,et al.  The mechanism of cysteine conjugate cytotoxicity in renal epithelial cells. Covalent binding leads to thiol depletion and lipid peroxidation. , 1990, The Journal of biological chemistry.

[21]  P. Jones,et al.  Differential nuclear protein binding to 5-azacytosine-containing DNA as a potential mechanism for 5-aza-2'-deoxycytidine resistance , 1987, Molecular and cellular biology.

[22]  D. Mccormick.  Sequence the Human Genome , 1986, Bio/Technology.

[23]  P. Barr,et al.  On the mechanism of inhibition of DNA-cytosine methyltransferases by cytosine analogs , 1983, Cell.

[24]  M. Harris.  Induction of thymidine kinase in enzyme-deficient chinese hamster cells , 1982, Cell.

[25]  Peter A. Jones,et al.  Cellular differentiation, cytidine analogs and DNA methylation , 1980, Cell.

[26]  M. Lübbert,et al.  DNA methylation inhibitors in the treatment of leukemias, myelodysplastic syndromes and hemoglobinopathies: clinical results and possible mechanisms of action. , 2000, Current topics in microbiology and immunology.

[27]  P. Jones,et al.  Inhibition of DNA methylation by 5-aza-2'-deoxycytidine suppresses the growth of human tumor cell lines. , 1998, Cancer research.

[28]  J. Herman,et al.  Alterations in DNA methylation: a fundamental aspect of neoplasia. , 1998, Advances in cancer research.

[29]  E. Estey,et al.  Results of decitabine therapy in the accelerated and blastic phases of chronic myelogenous leukemia , 1997, Leukemia.

[30]  P. Néve,et al.  Continuous infusion of low-dose 5-Aza-2′-deoxycytidine in elderly patients with high-risk myelodysplastic syndrome , 1997, Leukemia.