Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer

被引:14
|
作者
Wada, Miku [1 ]
Kukita, Asako [1 ]
Sone, Kenbun [1 ]
Hamamoto, Ryuji [2 ,3 ]
Kaneko, Syuzo [2 ]
Komatsu, Masaaki [2 ,3 ]
Takahashi, Yu [1 ]
Inoue, Futaba [1 ]
Kojima, Machiko [1 ]
Honjoh, Harunori [1 ]
Taguchi, Ayumi [1 ]
Kashiyama, Tomoko [1 ]
Miyamoto, Yuichiro [1 ]
Tanikawa, Michihiro [1 ]
Tsuruga, Tetsushi [1 ]
Mori-Uchino, Mayuyo [1 ]
Wada-Hiraike, Osamu [1 ]
Osuga, Yutaka [1 ]
Fujii, Tomoyuki [1 ]
机构
[1] Univ Tokyo, Dept Obstet & Gynecol, Fac Med, Bunkyo Ku, 7-3-1 Hongo, Tokyo 1138655, Japan
[2] Natl Canc Ctr, Div Mol Modificat & Canc Biol, Chuo Ku, 5-1-1 Tsukiji, Tokyo 1040045, Japan
[3] RIKEN Ctr Adv Intelligence Project, Canc Translat Res Team, Chuo Ku, 1-4-1 Nihonbashi, Tokyo 1030027, Japan
关键词
epigenetic modifier; histone methyltransferase; SETD8; high-grade serous ovarian cancer; UNC0379; HISTONE; METHYLATION; P53; ACTIVATION; EXPRESSION;
D O I
10.3390/biom10121686
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The histone methyltransferase SETD8, which methylates the lysine 20 of histone H4 (H4K20), is reportedly involved in human carcinogenesis along with nonhistone proteins such as p53. However, its expression profiles and functions in the context of high-grade serous ovarian carcinoma (HGSOC) are still unknown. The purpose of this study was to investigate the role of SETD8 in HGSOC. We performed quantitative real-time PCR and immunohistochemistry to detect the expression of SETD8 in HGSOC samples and normal ovarian specimens. Then, we assessed the effect of the inhibition of SETD8 expression using small interfering RNA (siRNA) and a selective inhibitor (UNC0379) on cell proliferation and apoptosis in HGSOC cells. The expression of SETD8 was significantly upregulated in clinical ovarian cancer specimens compared to that in the corresponding normal ovary. In addition, suppression of SETD8 expression in HGSOC cells with either siRNA or UNC0379 resulted in reduced levels of H4K20 monomethylation, inhibition of cell proliferation, and induction of apoptosis. Furthermore, UNC0379 showed a long-term antitumor effect against HGSOC cells, as demonstrated by colony-formation assays. SETD8 thus constitutes a promising therapeutic target for HGSOC, warranting further functional studies.
引用
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页码:1 / 12
页数:12
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