Abstract: Transcription factors, which represent an important class of proteins that play key roles in controlling cellular proliferation and cell cycle modulation, are attractive targets for cancer therapy. Previous researches have shown that the expression level of activating transcription factor 5 (ATF5) was frequently increased in glioma and its acetylation level was related to glioma. The purposes of this study were to explore the methylation level of ATF5 in clinical glioma tissues and to explore the effect of ATF5 methylation on the expression of ATF5 in glioma. Methylation of the promoter region of ATF5 was assayed by bisulfite-specific polymerase chain reaction (PCR) sequencing analysis in 35 cases of glioma and 5 normal tissues. Quantitative real-time PCR (qRT-PCR) was also performed to detect ATF5 mRNA expression in 35 cases of glioma and 5 normal tissues. Clinical data were collected from the patients and analyzed. The percentages of methylation of the ATF5 gene in the promoter region in healthy control, patients with well-differentiated glioma, and those with poorly differentiated glioma were 87.78%, 73.89%, and 47.70%, respectively. Analysis of the methylation status of the promoter region of the ATF5 gene showed a gradually decreased methylation level in poorly differentiated glioma, well-differentiated glioma, and normal tissues (P<0.05). There was also a significant difference between well-differentiated glioma and poorly differentiated glioma (P<0.05). ATF5 mRNA expression in glioma was significantly higher than that in the normal tissues (P<0.05). This study provides the first evidence that the methylation level of ATF5 decreased, and its mRNA expression was evidently up-regulated in glioma.

激活转录因子5启动子区甲基化水平的研究

[1]Adrien, L., Schlecht, N., Kawachi, N., et al., 2006. Classification of DNA methylation patterns in tumor cell genomes using a CpG island microarray. Cytogenet. Genome Res., 114(1):16-23.

[2]Chen, A., Qian, D., Wang, B., et al., 2012. ATF5 is overexpressed in epithelial ovarian carcinomas and interference with its function increases apoptosis through the downregulation of Bcl-2 in SKOV-3 cells. Int. J. Gynecol. Pathol., 31(6):532-537.

[3]Dluzen, D., Li, G., Tacelosky, D., et al., 2011. BCL-2 is a downstream target of ATF5 that mediates the prosurvival function of ATF5 in a cell type-dependent manner. J. Biol. Chem., 286(9):7705-7713.

[4]Doolittle, N.D., 2004. State of the science in brain tumor classification. Semin. Oncol. Nurs., 20(4):224-230.

[5]Gho, J.W., Ip, W.K., Chan, K.Y., et al., 2008. Re-expression of transcription factor ATF5 in hepatocellular carcinoma induces G2-M arrest. Cancer Res., 68(16):6743-6751.

[6]Greene, L.A., Lee, H.Y., Angelastro, J.M., 2009. The transcription factor ATF5: role in neurodevelopment and neural tumors. J. Neurochem., 108(1):11-22.

[7]Haakenson, J.K., Kester, M., Liu, D.X., 2012. The ATF/CREB family of transcription factors in breast cancer. In: Rebecca, A. (Ed.), Targeting New Pathways and Cell Death in Breast Cancer. InTech, p.71-84. Available from: http://www.intechopen.com/books/targeting-new-pathways-and-celldeath-in-breast-cancer/the-atf-creb-family-of-transcription-factors-in-breast-cancer [Accessed on Mar. 16, 2015]

[8]Herman, J.G., Baylin, S.B., 2003. Gene silencing in cancer in association with promoter hypermethylation. N. Engl. J. Med., 349(21):2042-2054.

[9]Hu, M., Wang, B., Qian, D., et al., 2012. Interference with ATF5 function enhances the sensitivity of human pancreatic cancer cells to paclitaxel-induced apoptosis. Anticancer Res., 32(10):4385-4394.

[10]Kim, S., Yu, S.S., Lee, I.S., et al., 1999. Human cytomegalovirus IE1 protein activates AP-1 through a cellular protein kinase(s). J. Gen. Virol., 80(4):961-969.

[11]Li, G., Li, W., Angelastro, J. M., et al., 2009. Identification of a novel DNA binding site and a transcriptional target for activating transcription factor 5 in C6 glioma and MCF-7 breast cancer cells. Mol. Cancer Res., 7(6):933-943.

[12]Liu, D.X., Qian, D., Wang, B., et al., 2011. p300-Dependent ATF5 acetylation is essential for Egr-1 gene activation and cell proliferation and survival. Mol. Cell. Biol., 31(18):3906-3916.

[13]Mason, J.L., Angelastro, J.M., Ignatova, T.N., et al., 2005. ATF5 regulates the proliferation and differentiation of oligodendrocytes. Mol. Cell. Neurosci., 29(3):372-380.

[14]Mora, J., Cheung, N.K., Chen, L., et al., 2001. Loss of heterozygosity at 19q13.3 is associated with locally aggressive neuroblastoma. Clin. Cancer Res., 7(5):1358-1361.

[15]Pascual, M., Gómez-Lechón, M.J., Castell, J.V., et al., 2008. ATF5 is a highly abundant liver-enriched transcription factor that cooperates with constitutive androstane receptor in the transactivation of CYP2B6: implications in hepatic stress responses. Drug Metab. Dispos., 36(6):1063-1072.

[16]Razin, A., 1998. CpG methylation, chromatin structure and gene silencing—a three-way connection. EMBO J., 17(17):4905-4908.

[17]Sheng, Z., Evans, S.K., Green, M.R., 2010a. An activating transcription factor 5-mediated survival pathway as a target for cancer therapy. Oncotarget, 1(6):457.

[18]Sheng, Z., Li, L., Zhu, L.J., et al., 2010b. A genome-wide RNA interference screen reveals an essential CREB3L2-ATF5-MCL1 survival pathway in malignant glioma with therapeutic implications. Nat. Med., 16(6):671-677.

[19]Singh, N., Paterson, D.L., 2000. Encephalitis caused by human herpesvirus-6 in transplant recipients: relevance of a novel neurotropic virus. Transplantation, 69(12):2474-2479.

[20]Wang, A., Arantes, S., Yan, L., et al., 2008. The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis. BMC Cancer, 8(1):268.

[21]Wang, S.Z., Ou, J., Zhu, L.J., 2012. Transcription factor ATF5 is required for terminal differentiation and survival of olfactory sensory neurons. PNAS, 109(45):18589-18594.

[22]Wang, T., Qian, D., Hu, M., et al., 2014. Human cytomegalovirus inhibits apoptosis by regulating the activating transcription factor 5 signaling pathway in human malignant glioma cells. Oncol. Lett., 8(3):1051-1057.

[23]Wu, Y., Wu, B., Chen, R., et al., 2014. High ATF5 expression is a favorable prognostic indicator in patients with hepatocellular carcinoma after hepatectomy. Med. Oncol., 31(11):1-6.

[24]Yurochko, A.D., Mayo, M.W., Poma, E.E., et al., 1997. Induction of the transcription factor Sp1 during human cytomegalovirus infection mediates upregulation of the p65 and p105/p50 NF-κB promoters. J. Virol., 71(6):4638-4648.