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The Histone Methyltransferase SETD8 Regulates the Expression of Tumor Suppressor Genes via H4K20 Methylation and the p53 Signaling Pathway in Endometrial Cancer Cells

2022; Multidisciplinary Digital Publishing Institute; Volume: 14; Issue: 21 Linguagem: Inglês

10.3390/cancers14215367

2072-6694

Asako Kukita, Kenbun Sone, Syuzo Kaneko, Eiryo Kawakami, Shinya Oki, Machiko Kojima, Miku Wada, Yusuke Toyohara, Yu Takahashi, Futaba Inoue, Saki Tanimoto, Ayumi Taguchi, Tomohiko Fukuda, Yuichiro Miyamoto, Michihiro Tanikawa, Mayuyo Mori‐Uchino, Tetsushi Tsuruga, Takayuki Iriyama, Yōko Matsumoto, Kazunori Nagasaka, Osamu Wada‐Hiraike, Katsutoshi Oda, Ryuji Hamamoto, Yutaka Osuga,

RNA modifications and cancer

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. SETD8 is an important gene for carcinogenesis and progression of endometrial cancer via H4K20 methylation.