Oncotarget

Research Papers:

Overexpression of KDM5B/JARID1B is associated with poor prognosis in hepatocellular carcinoma

Yoshinobu Shigekawa, Shinya Hayami _, Masaki Ueno, Atsushi Miyamoto, Norihiko Suzaki, Manabu Kawai, Seiko Hirono, Ken-ichi Okada, Ryuji Hamamoto and Hiroki Yamaue

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Oncotarget. 2018; 9:34320-34335. https://doi.org/10.18632/oncotarget.26144

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Abstract

Yoshinobu Shigekawa1, Shinya Hayami1, Masaki Ueno1, Atsushi Miyamoto1, Norihiko Suzaki1, Manabu Kawai1, Seiko Hirono1, Ken-ichi Okada1, Ryuji Hamamoto2 and Hiroki Yamaue1

1Second Department of Surgery, School of Medicine, Wakayama Medical University, Wakayama, Japan

2Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, Tokyo, Japan

Correspondence to:

Shinya Hayami, email: shin-8@wakayama-med.ac.jp

Keywords: hepatocellular carcinoma (HCC); epigenetics; histone demethylase; KDM5B/JARID1B

Received: March 24, 2018    Accepted: September 04, 2018    Published: September 28, 2018

ABSTRACT

Background & aims: Hepatocellular carcinoma (HCC) has high potential for recurrence, even in curative operative cases. Although several molecular-targeting drugs have been applied to recurrent HCC, their effectiveness has been limited. This study therefore aims to develop novel cancer drugs through protein methylation.

Methods: We investigated the role of KDM5B/JARID1B, a member of JmjC histone demethylase, in HCC. Expression profiles of KDM5B were examined by immunohistochemical analysis in 105 HCC clinical tissue samples. To examine functional effects of KDM5B using HCC cell lines, we performed loss-of-function analysis treated with KDM5B-specific small interfering RNAs (siKDM5B).

Results: All HCC cases were divided into KDM5B-positive expression group (n=54) and negative expression group (n=51). In five-year overall survival, KDM5B-positive group had poorer prognosis than KDM5B-negative (61% vs 77%, p=0.047). KDM5B-positive group had much poorer prognosis than that of the negative group, especially in HCC derived from persistent infection of hepatitis B virus (HBV) or hepatitis C virus (HCV) (54% vs 78%, p=0.015). Multivariate analysis indicated that KDM5B was the strongest risk factor for poor prognosis, especially in HCC derived from HBV/HCV. Inhibition of KDM5B could significantly suppress HCC cell proliferation through no promotion from G1 to S phase. Real-time PCR and Western blotting demonstrated that E2F1/E2F2 were downstream genes of KDM5B.

Conclusions: Overexpression of KDM5B results in poor prognosis in HCC that especially derived from HBV/HCV. KDM5B appears to be an ideal target for the development of anti-cancer drugs.


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