Abstract
BackgroundGlobal DNA hypomethylation contributes to oncogenesis through various mechanisms. The level of long interspersed nucleotide element-1 (LINE- 1) methylation is considered a surrogate marker of global DNA methylation, and is attracting interest as a good predictor of cancer prognosis. However, the mechanism how LINE-1 (global DNA) methylation is controlled in cancer cells remains to be fully elucidated. Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) plays a crucial role in DNA methylation. UHRF1 is overexpressed in many cancers, and UHRF1 overexpression may be a mechanism underlying DNA hypomethylation in cancer cells. Nonetheless, the relationship between UHRF1, LINE-1 methylation level, and clinical outcome in esophageal squamous cell carcinoma (ESCC) remains unclear.ResultsIn ESCC cell lines, vector-mediated UHRF1 overexpression caused global DNA (LINE-1) hypomethylation and, conversely, UHRF1 knockdown using siRNA increased the global DNA methylation level. In ESCC tissues, UHRF1 expression was significantly associated with LINE-1 methylation levels. Furthermore, UHRF1 overexpression correlated with poor prognosis in our cohort of 160 ESCC patients.Materials and MethodsThe relationships between UHRF1 expression and LINE-1 methylation level (i.e., global DNA methylation level) were investigated using ESCC tissues and cell lines. In addition, we examined the correlation between UHRF1 expression, LINE-1 methylation, and clinical outcome in patients with ESCC.ConclusionsOur results suggest that UHRF1 is a key epigenetic regulator of DNA methylation and might be a potential target for cancer treatment.
Highlights
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors [1]
In esophageal squamous cell carcinoma (ESCC) tissues, UHRF1 expression was significantly associated with LINE-1 methylation levels
Our results suggest that UHRF1 is a key epigenetic regulator of DNA methylation and might be a potential target for cancer treatment
Summary
Esophageal squamous cell carcinoma (ESCC) is one of the most malignant tumors [1]. Despite remarkable progress in the advance of multidisciplinary treatments combining surgery, chemotherapy and/or radiotherapy, the outcome of ESCC patients remains unfavorable even after complete resection [2,3,4]. Global DNA hypomethylation contributes to oncogenesis through various mechanisms, including genomic instability [10,11,12]. Because long interspersed nucleotide element-1 (LINE-1) represents a considerable part of human genome (approximately 17%), LINE-1 methylation levels have been considered as a surrogate marker of global DNA methylation [13]. The mechanism by which LINE-1 (and global DNA) methylation is controlled in ESCC cells remains to be fully explored. The level of long interspersed nucleotide element-1 (LINE- 1) methylation is considered a surrogate marker of global DNA methylation, and is attracting interest as a good predictor of cancer prognosis. The mechanism how LINE-1 (global DNA) methylation is controlled in cancer cells remains to be fully elucidated. The relationship between UHRF1, LINE-1 methylation level, and clinical outcome in esophageal squamous cell carcinoma (ESCC) remains unclear
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