Kukita Asako, Sone Kenbun, Kaneko Syuzo, Kawakami Eiryo, Oki Shinya, Kojima Machiko, Wada Miku, Toyohara Yusuke, Takahashi Yu, Inoue Futaba, Tanimoto Saki, Taguchi Ayumi, Fukuda Tomohiko, Miyamoto Yuichiro, Tanikawa Michihiro, Mori-Uchino Mayuyo, Tsuruga Tetsushi, Iriyama Takayuki, Matsumoto Yoko, Nagasaka Kazunori, Wada-Hiraike Osamu, Oda Katsutoshi, Hamamoto Ryuji, Osuga Yutaka
Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
Cancers (Basel). 2022 Oct 31;14(21):5367. doi: 10.3390/cancers14215367.
The histone methyltransferase SET domain-containing protein 8 (SETD8), which methylates histone H4 lysine 20 (H4K20) and non-histone proteins such as p53, plays key roles in human carcinogenesis. Our aim was to determine the involvement of SETD8 in endometrial cancer and its therapeutic potential and identify the downstream genes regulated by SETD8 via H4K20 methylation and the p53 signaling pathway. We examined the expression profile of SETD8 and evaluated whether SETD8 plays a critical role in the proliferation of endometrial cancer cells using small interfering RNAs (siRNAs). We identified the prognostically important genes regulated by SETD8 via H4K20 methylation and p53 signaling using chromatin immunoprecipitation sequencing, RNA sequencing, and machine learning. We confirmed that SETD8 expression was elevated in endometrial cancer tissues. Our in vitro results suggest that the suppression of SETD8 using siRNA or a selective inhibitor attenuated cell proliferation and promoted the apoptosis of endometrial cancer cells. In these cells, SETD8 regulates genes via H4K20 methylation and the p53 signaling pathway. We also identified the prognostically important genes related to apoptosis, such as those encoding KIAA1324 and TP73, in endometrial cancer. is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.
组蛋白甲基转移酶含SET结构域蛋白8（SETD8）可使组蛋白H4赖氨酸20（H4K20）以及诸如p53等非组蛋白发生甲基化，在人类致癌过程中发挥关键作用。我们的目的是确定SETD8在子宫内膜癌中的作用及其治疗潜力，并通过H4K20甲基化和p53信号通路鉴定受SETD8调控的下游基因。我们检测了SETD8的表达谱，并使用小干扰RNA（siRNA）评估SETD8在子宫内膜癌细胞增殖中是否发挥关键作用。我们通过染色质免疫沉淀测序、RNA测序和机器学习，鉴定了受SETD8通过H4K20甲基化和p53信号通路调控的对预后重要的基因。我们证实SETD8在子宫内膜癌组织中的表达升高。我们的体外实验结果表明，使用siRNA或选择性抑制剂抑制SETD8可减弱细胞增殖并促进子宫内膜癌细胞的凋亡。在这些细胞中，SETD8通过H4K20甲基化和p53信号通路调控基因。我们还在子宫内膜癌中鉴定了与凋亡相关的对预后重要的基因，例如编码KIAA1324和TP73的基因。SETD8是通过H4K20甲基化在子宫内膜癌发生和进展中起重要作用的基因。
