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

Kenichi Nakamura; Yoshifumi Baba; Keisuke Kosumi; Kazuto Harada; Hironobu Shigaki; Keisuke Miyake; Yuki Kiyozumi; Mayuko Ohuchi; Junji Kurashige; Takatsugu Ishimoto; Masaaki Iwatsuki; Yasuo Sakamoto; Naoya Yoshida; Masayuki Watanabe; Mitsuyoshi Nakao; Hideo Baba

doi:10.18632/oncotarget.11067

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Research Papers:

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

Kenichi Nakamura, Yoshifumi Baba, Keisuke Kosumi, Kazuto Harada, Hironobu Shigaki, Keisuke Miyake, Yuki Kiyozumi, Mayuko Ohuchi, Junji Kurashige, Takatsugu Ishimoto, Masaaki Iwatsuki, Yasuo Sakamoto, Naoya Yoshida, Masayuki Watanabe, Mitsuyoshi Nakao and Hideo Baba _

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Oncotarget. 2016; 7:57821-57831. https://doi.org/10.18632/oncotarget.11067

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Abstract

Kenichi Nakamura1, Yoshifumi Baba1, Keisuke Kosumi1, Kazuto Harada1, Hironobu Shigaki1, Keisuke Miyake1, Yuki Kiyozumi1, Mayuko Ohuchi1, Junji Kurashige1, Takatsugu Ishimoto1, Masaaki Iwatsuki1, Yasuo Sakamoto1, Naoya Yoshida1, Masayuki Watanabe2, Mitsuyoshi Nakao3, Hideo Baba1

1Department of Gastroenterological Surgery, Graduate School of Medical Science, Kumamoto University, Kumamoto, Japan

2Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

3Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan

Correspondence to:

Hideo Baba, email: [email protected]

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.

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Research Papers:

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

Abstract