1. Academic Validation
  2. Epigenetic Modifier SETD8 as a Therapeutic Target for High-Grade Serous Ovarian Cancer

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

  • Biomolecules. 2020 Dec 16;10(12):1686. doi: 10.3390/biom10121686.
Miku Wada 1 Asako Kukita 1 Kenbun Sone 1 Ryuji Hamamoto 2 3 Syuzo Kaneko 2 Masaaki Komatsu 2 3 Yu Takahashi 1 Futaba Inoue 1 Machiko Kojima 1 Harunori Honjoh 1 Ayumi Taguchi 1 Tomoko Kashiyama 1 Yuichiro Miyamoto 1 Michihiro Tanikawa 1 Tetsushi Tsuruga 1 Mayuyo Mori-Uchino 1 Osamu Wada-Hiraike 1 Yutaka Osuga 1 Tomoyuki Fujii 1
Affiliations

Affiliations

  • 1 Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
  • 2 Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
  • 3 Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan.
Abstract

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.

Keywords

H4K20 monomethylation; SETD8; UNC0379; epigenetic modifier; high-grade serous ovarian cancer; histone methyltransferase.

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