Department of Otolaryngology, Head and Neck Cancer Research Division, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
PLoS One. 2012;7(9):e44951. doi: 10.1371/journal.pone.0044951. Epub 2012 Sep 27.
The human cysteine dioxygenase 1 (CDO1) gene is a non-heme structured, iron-containing metalloenzyme involved in the conversion of cysteine to cysteine sulfinate, and plays a key role in taurine biosynthesis. In our search for novel methylated gene promoters, we have analyzed differential RNA expression profiles of colorectal cancer (CRC) cell lines with or without treatment of 5-aza-2'-deoxycytidine. Among the genes identified, the CDO1 promoter was found to be differentially methylated in primary CRC tissues with high frequency compared to normal colon tissues. In addition, a statistically significant difference in the frequency of CDO1 promoter methylation was observed between primary normal and tumor tissues derived from breast, esophagus, lung, bladder and stomach. Downregulation of CDO1 mRNA and protein levels were observed in cancer cell lines and tumors derived from these tissue types. Expression of CDO1 was tightly controlled by promoter methylation, suggesting that promoter methylation and silencing of CDO1 may be a common event in human carcinogenesis. Moreover, forced expression of full-length CDO1 in human cancer cells markedly decreased the tumor cell growth in an in vitro cell culture and/or an in vivo mouse model, whereas knockdown of CDO1 increased cell growth in culture. Our data implicate CDO1 as a novel tumor suppressor gene and a potentially valuable molecular marker for human cancer.
人类半胱氨酸双加氧酶 1（CDO1）基因是一种非血红素结构的含铁金属酶，参与半胱氨酸向半胱氨酸亚磺酸的转化，在牛磺酸生物合成中发挥关键作用。在寻找新的甲基化基因启动子的过程中，我们分析了用 5-氮杂-2'-脱氧胞苷处理或未处理的结直肠癌细胞系的差异 RNA 表达谱。在所鉴定的基因中，发现 CDO1 启动子在原发性 CRC 组织中与正常结肠组织相比存在高频差异甲基化。此外，在源自乳腺、食管、肺、膀胱和胃的原发性正常和肿瘤组织之间，观察到 CDO1 启动子甲基化的频率存在统计学显著差异。在这些组织类型的癌细胞系和肿瘤中观察到 CDO1 mRNA 和蛋白水平下调。CDO1 的表达受到启动子甲基化的严格控制，表明启动子甲基化和 CDO1 沉默可能是人类癌症发生的常见事件。此外，在人类癌细胞中强制表达全长 CDO1 可显著降低体外细胞培养和/或体内小鼠模型中的肿瘤细胞生长，而 CDO1 的敲低则增加了培养中的细胞生长。我们的数据表明 CDO1 是一种新的肿瘤抑制基因，并且是人类癌症的潜在有价值的分子标志物。
