Division of Bioinformatics and Chemical Genomics, Department of System Chemotherapy and Molecular Sciences, Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo, Kyoto 606-8501, Japan and Department of Clinical Oncology, Kyoto Pharmaceutical University, Kyoto 607-8414, Japan.
J Biochem. 2013 Oct;154(4):355-62. doi: 10.1093/jb/mvt063. Epub 2013 Jul 12.
Human chromosome 7 open reading frame 24 (C7orf24)/γ-glutamyl cyclotransferase has been suggested to be a potential diagnostic marker for several cancers, including carcinomas in the bladder urothelium, breast and endometrial epithelium. We here investigated the epigenetic regulation of the human C7orf24 promoter in normal diploid ARPE-19 and IMR-90 cells and in the MCF-7 and HeLa cancer cell lines to understand the transcriptional basis for the malignant-associated high expression of C7orf24. Chromatin immunoprecipitation analysis revealed that histone modifications associated with active chromatin were enriched in the proximal region but not in the distal region of the C7orf24 promoter in HeLa and MCF-7 cells. In contrast, elevated levels of histone modifications leading to transcriptional repression and accumulation of heterochromatin proteins in the C7orf24 promoter were observed in the ARPE-19 and IMR-90 cells, compared to the levels in HeLa and MCF-7 cancer cells. In parallel, the CpG island of the C7orf24 promoter was methylated to a greater extent in the normal cells than in the cancer cells. These results suggest that the transcriptional silencing of the C7orf24 gene in the non-malignant cells is elicited through heterochromatin formation in its promoter region; aberrant expression of C7orf24 associated with malignant alterations results from changes in chromatin dynamics.
人类染色体 7 开放阅读框 24（C7orf24）/γ-谷氨酰环转移酶被认为是几种癌症的潜在诊断标志物，包括膀胱尿路上皮癌、乳腺癌和子宫内膜上皮癌。我们在此研究了正常二倍体 ARPE-19 和 IMR-90 细胞以及 MCF-7 和 HeLa 癌细胞系中人类 C7orf24 启动子的表观遗传调控，以了解 C7orf24 与恶性相关的高表达的转录基础。染色质免疫沉淀分析显示，与活性染色质相关的组蛋白修饰在 HeLa 和 MCF-7 细胞中富含 C7orf24 启动子的近端区域，但不在其远端区域富集。相比之下，在 ARPE-19 和 IMR-90 细胞中观察到 C7orf24 启动子中导致转录抑制和异染色质蛋白积累的组蛋白修饰水平升高，与 HeLa 和 MCF-7 癌细胞中的水平相比。同时，C7orf24 启动子的 CpG 岛在正常细胞中比在癌细胞中甲基化程度更高。这些结果表明，非恶性细胞中 C7orf24 基因的转录沉默是通过其启动子区域异染色质的形成引起的；与恶性改变相关的 C7orf24 的异常表达是由染色质动力学的变化引起的。
