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

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; Yoko Matsumoto; Kazunori Nagasaka; Osamu Wada-Hiraike; Katsutoshi Oda; Ryuji Hamamoto; Yutaka Osuga

doi:10.3390/cancers14215367

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

Cancers (Basel). 2022 Oct 31;14(21):5367. doi: 10.3390/cancers14215367.

Authors

Asako Kukita¹, Kenbun Sone¹, Syuzo Kaneko^{2

3}, Eiryo Kawakami⁴, Shinya Oki⁵, Machiko Kojima⁶, Miku Wada¹, Yusuke Toyohara¹, Yu Takahashi¹, Futaba Inoue¹, Saki Tanimoto¹, Ayumi Taguchi¹, Tomohiko Fukuda¹, Yuichiro Miyamoto¹, Michihiro Tanikawa¹, Mayuyo Mori-Uchino¹, Tetsushi Tsuruga¹, Takayuki Iriyama¹, Yoko Matsumoto¹, Kazunori Nagasaka⁷, Osamu Wada-Hiraike¹, Katsutoshi Oda⁸, Ryuji Hamamoto^{2

3}, Yutaka Osuga¹

Affiliations

¹ Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
² Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo 104-0045, Japan.
³ Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, Tokyo 103-0027, Japan.
⁴ Graduate School of Medicine, Chiba University, Chiba 263-8522, Japan.
⁵ National Hospital Organization Tokyo Medical Center, Tokyo 152-8902, Japan.
⁶ Tazuke Kofukai, Medical Research Institute, Kitano Hospital, Osaka 530-8480, Japan.
⁷ Department of Obstetrics and Gynecology, Teikyo University School of Medicine, Tokyo 173-0003, Japan.
⁸ Division of Integrated Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.

Abstract

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.

Keywords: SETD8 TP73; chromatin immunoprecipitation sequencing; endometrial cancer; histone methyltransferases; machine learning.

Grants and funding

This work was financially supported by a Grant-in-Aid for Scientific Research, grant numbers 18K09249, 15K10705, and 17K11268, and a Grant-in-Aid for Research Activity Start-up, grant number 15H06173, from The Ministry of Education, Culture, Sports, Science and Technology of Japan. This research was also funded by the Project for Cancer Research and Therapeutic Evolution from the Japan Agency for Medical Research and Development, grant number 17K11268. K.S. received a research grant from Daiichi-Sankyo Co., Ltd. (TaNeDS project). The research reported in this work was also supported by the Takeda Science Foundation (to S.K.).