Department of Obstetrics and Gynecology, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo 113-8655, Japan.
Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Biomolecules. 2020 Dec 16;10(12):1686. doi: 10.3390/biom10121686.
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.
组蛋白甲基转移酶 SETD8 可将组蛋白 H4 的赖氨酸 20 甲基化（H4K20），据报道，它与非组蛋白蛋白（如 p53）一起参与人类癌症的发生。然而，其在高级别浆液性卵巢癌（HGSOC）中的表达谱和功能仍不清楚。本研究旨在探讨 SETD8 在 HGSOC 中的作用。我们通过定量实时 PCR 和免疫组织化学检测了 SETD8 在 HGSOC 样本和正常卵巢标本中的表达。然后，我们评估了使用小干扰 RNA（siRNA）和选择性抑制剂（UNC0379）抑制 SETD8 表达对 HGSOC 细胞增殖和凋亡的影响。与相应的正常卵巢相比，SETD8 在临床卵巢癌标本中的表达明显上调。此外，用 siRNA 或 UNC0379 抑制 HGSOC 细胞中的 SETD8 表达导致 H4K20 单甲基化水平降低、细胞增殖抑制和凋亡诱导。此外，UNC0379 在集落形成实验中显示出对 HGSOC 细胞的长期抗肿瘤作用。因此，SETD8 是 HGSOC 有前途的治疗靶点，值得进一步进行功能研究。
