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

Research output: Contribution to journalArticle

13 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)57821-57831
Number of pages11
JournalOncotarget
Volume7
Issue number36
DOIs
Publication statusPublished - Jan 1 2016

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DNA Methylation
Methylation
DNA
Neoplasms
Long Interspersed Nucleotide Elements
RING Finger Domains
Cell Line
Ubiquitin
Epigenomics
Small Interfering RNA
Esophageal Squamous Cell Carcinoma
Carcinogenesis
Biomarkers

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

Nakamura, K., Baba, Y., Kosumi, K., Harada, K., Shigaki, H., Miyake, K., ... Baba, H. (2016). UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma. Oncotarget, 7(36), 57821-57831. https://doi.org/10.18632/oncotarget.11067

UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma. / Nakamura, Kenichi; Baba, Yoshifumi; Kosumi, Keisuke; Harada, Kazuto; Shigaki, Hironobu; Miyake, Keisuke; Kiyozumi, Yuki; Ohuchi, Mayuko; Kurashige, Junji; Ishimoto, Takatsugu; Iwatsuki, Masaaki; Sakamoto, Yasuo; Yoshida, Naoya; Watanabe, Masayuki; Nakao, Mitsuyoshi; Baba, Hideo.

In: Oncotarget, Vol. 7, No. 36, 01.01.2016, p. 57821-57831.

Research output: Contribution to journalArticle

Nakamura, K, Baba, Y, Kosumi, K, Harada, K, Shigaki, H, Miyake, K, Kiyozumi, Y, Ohuchi, M, Kurashige, J, Ishimoto, T, Iwatsuki, M, Sakamoto, Y, Yoshida, N, Watanabe, M, Nakao, M & Baba, H 2016, 'UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma', Oncotarget, vol. 7, no. 36, pp. 57821-57831. https://doi.org/10.18632/oncotarget.11067
Nakamura, Kenichi ; Baba, Yoshifumi ; Kosumi, Keisuke ; Harada, Kazuto ; Shigaki, Hironobu ; Miyake, Keisuke ; Kiyozumi, Yuki ; Ohuchi, Mayuko ; Kurashige, Junji ; Ishimoto, Takatsugu ; Iwatsuki, Masaaki ; Sakamoto, Yasuo ; Yoshida, Naoya ; Watanabe, Masayuki ; Nakao, Mitsuyoshi ; Baba, Hideo. / UHRF1 regulates global DNA hypomethylation and is associated with poor prognosis in esophageal squamous cell carcinoma. In: Oncotarget. 2016 ; Vol. 7, No. 36. pp. 57821-57831.
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AU - Nakamura, Kenichi

AU - Baba, Yoshifumi

AU - Kosumi, Keisuke

AU - Harada, Kazuto

AU - Shigaki, Hironobu

AU - Miyake, Keisuke

AU - Kiyozumi, Yuki

AU - Ohuchi, Mayuko

AU - Kurashige, Junji

AU - Ishimoto, Takatsugu

AU - Iwatsuki, Masaaki

AU - Sakamoto, Yasuo

AU - Yoshida, Naoya

AU - Watanabe, Masayuki

AU - Nakao, Mitsuyoshi

AU - Baba, Hideo

PY - 2016/1/1

Y1 - 2016/1/1

N2 - 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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