Abstract
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.
Highlights
Cancer is caused by aberrant gene regulation, including inactivation of negative regulators of cell proliferation and activation of positive regulators
In our search for genes epigenetically silenced in human colorectal cancer (CRC), we performed a combination of pharmacological unmasking and subsequent differential microarray analysis using microarrays containing 22,284 transcripts (Affymetrix) [26]
To investigate whether cysteine dioxygenase 1 (CDO1) expression is regulated by promoter methylation, we searched for CpG islands in the CDO1 promoter by using the online accessible software Methprimer
Summary
Cancer is caused by aberrant gene regulation, including inactivation of negative regulators of cell proliferation (including tumor suppressor genes; TSG) and activation of positive regulators (such as oncogenes). In addition to genetic alterations involving mutations of oncogenes and TSGs, carcinogenic process can occur through epigenetic changes in gene promoters [1]. Epigenetic changes, heritable changes in gene expression that occur without changes to the DNA sequence, contribute to the development and progression of tumor cells [2] and are considered to be hallmarks of cancer. CpG islands are not usually methylated in normal cells [3], but aberrant hypermethylation in the CpG islands which leads to transcriptional inactivation and gene silencing can be early events in carcinogenesis and is considered to be a common mechanism of loss of TSG function in human cancers [1,4]. Knowledge of methylation patterns across the genome can help to identify key TSGs inactivated during tumor formation [6,7,8]
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