UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma

// Kenichi Nakamura 1 , Yoshifumi Baba 1 , Keisuke Kosumi 1 , Kazuto Harada 1 , Hironobu Shigaki 1 , Keisuke Miyake 1 , Yuki Kiyozumi 1 , Mayuko Ohuchi 1 , Junji Kurashige 1 , Takatsugu Ishimoto 1 , Masaaki Iwatsuki 1 , Yasuo Sakamoto 1 , Naoya Yoshida 1 , Masayuki Watanabe 2 , Mitsuyoshi Nakao 3 , Hideo Baba 1 1 Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan 2 Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan 3 Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan Correspondence to: Hideo Baba, email: hdobaba@kumamoto-u.ac.jp Keywords: LINE-1, methylation, esophageal cancer, prognosis, UHRF1 Received: March 24, 2016 Accepted: July 19, 2016 Published: August 05, 2016 ABSTRACT Background: Global 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. Results: In 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 Methods: The 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. Conclusions: Our results suggest that UHRF1 is a key epigenetic regulator of DNA methylation and might be a potential target for cancer treatment.