Abstract 2776: The relationship between UHRF1 overexpression and LINE-1 hypomethylation in esophageal squamous cell carcinoma

Abstract

Abstract Background: Global DNA hypomethylation contributes to oncogenesis through multiple mechanism. The level of long interspersed nucleotide element-1 (LINE-1) methylation is regarded as a surrogate marker of global DNA methylation, and is drawing interest as a good indicator for predicting cancer prognosis. However, the mechanism by which LINE-1 (global DNA) methylation is controlled in cancer cells remains to be fully explored. Ubiquitin-like with PHD and RING finger domain 1 (UHRF1) plays an essential role in DNA methylation. Previous studies have demonstrated that UHRF1 overexpression might be a mechanism of underlying DNA hypomethylation in hepatocellular carcinoma, and contribute to poor prognosis. Nonetheless, the epigenetic role of UHRF1 in esophageal squamous cell carcinoma (ESCC) remains unclear. Methods: Using 16 frozen tissues (matched pairs of cancer and normal epithelium), and 160 curatively resected esophageal cancer specimens, we analyzed the relationship between UHRF1 expression, LINE-1 methylation levels and patient outcome. We measured UHRF1 expression by real-time PCR and immunohistochemistry, and LINE-1 methylation levels by bisulfite- pyrosequencing technology. In addition, to investigate the relationships between UHRF1 expression and LINE-1 methylation level (i.e., global DNA methylation level) using UHRF1 overexpression vector and siRNA for UHRF1 with ESCC tissues and ESCC cell lines. Results: In ESCC tissues, UHRF1 expression were significantly associated with LINE-1 methylation levels, and UHRF1 overexpression correlated with poor prognosis in our cohort of 160 ESCC patients. Furthermore, UHRF1 vector-mediated overexpression caused LINE-1 (global DNA) hypomethylation, and conversely, UHRF1 knockdown using siRNA increased DNA methylation in ESCC cell lines. Conclusion: These results may suggest that UHRF1 is an epigenetic key regulator of DNA methylation, moreover, can be applicable to attractive cancer therapies. Citation Format: Kenichi Nakamura, Yoshifumi Baba, Keisuke Kosumi, Kazuto Harada, Hironobu Shigaki, Keisuke Miyake, Junji Kurashige, Takatsugu Ishimoto, Masaaki Iwatsuki, Naoya Yoshida, Hideo Baba. The relationship between UHRF1 overexpression and LINE-1 hypomethylation in esophageal squamous cell carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2776.