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

Miku Wada,Yu Takahashi,Tomoyuki Fujii,Mayuyo Mori-Uchino,Yuichiro Miyamoto,Harunori Honjoh,Yutaka Osuga,Syuzo Kaneko,Ayumi Taguchi,Machiko Kojima,Osamu Wada-Hiraike,Tetsushi Tsuruga,Masaaki Komatsu,Ryuji Hamamoto,Asako Kukita,Kenbun Sone,Michihiro Tanikawa,Tomoko Kashiyama,Futaba Inoue

doi:10.3390/biom10121686

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.

Highlights

Patients with ovarian cancer have the poorest prognosis among all individuals with gynecological cancers
To determine whether histone methyltransferases constitute an appropriate therapeutic target for high-grade serous ovarian carcinoma (HGSOC), we examined the expression levels of different histone methyltransferases in HGSOC specimens by quantitative real-time PCR
The results showed that SETD8 was significantly overexpressed in HGSOC samples compared to the expression seen in normal ovarian tissue (Figure 1A)

Summary

Introduction

Patients with ovarian cancer have the poorest prognosis among all individuals with gynecological cancers. Over 2 × 106 new cases of ovarian cancer are reported annually, along with ~1 × 105 reported ovarian-cancer-related deaths [1]. High-grade serous ovarian carcinoma (HGSOC) is one of the most deadly ovarian cancer types because patients with HGSOC are mainly diagnosed at an advanced stage of the disease [2]. Frequent gene alterations such as those in TP53 and BRCA1/2 are observed in HGSOC cases. Some patients with HGSOC harbor germline mutations in BRCA1/2, which are related to hereditary breast and ovarian cancer syndrome [3]. It is necessary to develop new, more effective molecular targeting agents [3]

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Results