Inhibition of protein arginine methyltransferase 6 activates interferon signaling and induces the apoptosis of endometrial cancer cells via histone modification

Inoue,Futaba; Inoue,Futaba; Sone,Kenbun; Sone,Kenbun; Kumegawa,Kohei; Kumegawa,Kohei; Hachijo,Ryuta; Hachijo,Ryuta; Suzuki,Eri; Suzuki,Eri; Tanimoto,Saki; Tanimoto,Saki; Tsuboyama,Natsumi; Tsuboyama,Natsumi; Kato,Kosuke; Kato,Kosuke; Toyohara,Yusuke; Toyohara,Yusuke; Takahashi,Yu; Takahashi,Yu; Kusakabe,Misako; Kusakabe,Misako; Kukita,Asako; Kukita,Asako; Honjoh,Harunori; Honjoh,Harunori; Nishijima,Akira; Nishijima,Akira; Taguchi,Ayumi; Taguchi,Ayumi; Miyamoto,Yuichiro; Miyamoto,Yuichiro; Tanikawa,Michihiro; Tanikawa,Michihiro; Iriyama,Takayuki; Iriyama,Takayuki; Mori,Mayuyo; Mori,Mayuyo; Wada‑Hiraike,Osamu; Wada‑Hiraike,Osamu; Oda,Katsutoshi; Oda,Katsutoshi; Suzuki,Hiromu; Suzuki,Hiromu; Maruyama,Reo; Maruyama,Reo; Osuga,Yutaka; Osuga,Yutaka

doi:10.3892/ijo.2024.5620

Inhibition of protein arginine methyltransferase 6 activates interferon signaling and induces the apoptosis of endometrial cancer cells via histone modification

Authors:
- Futaba Inoue
- Kenbun Sone
- Kohei Kumegawa
- Ryuta Hachijo
- Eri Suzuki
- Saki Tanimoto
- Natsumi Tsuboyama
- Kosuke Kato
- Yusuke Toyohara
- Yu Takahashi
- Misako Kusakabe
- Asako Kukita
- Harunori Honjoh
- Akira Nishijima
- Ayumi Taguchi
- Yuichiro Miyamoto
- Michihiro Tanikawa
- Takayuki Iriyama
- Mayuyo Mori
- Osamu Wada‑Hiraike
- Katsutoshi Oda
- Hiromu Suzuki
- Reo Maruyama
- Yutaka Osuga
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Affiliations: Department of Obstetrics and Gynecology, Graduate School of Medicine, The University of Tokyo, Tokyo 113‑8655, Japan, Cancer Cell Diversity Project, NEXT‑Ganken Program, Japanese Foundation for Cancer Research, Tokyo 135‑8550, Japan, Division of Integrative Genomics, Graduate School of Medicine, The University of Tokyo, Tokyo 113‑8655, Japan, Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
Published online on: January 30, 2024 https://doi.org/10.3892/ijo.2024.5620
Article Number: 32
Copyright: © Inoue et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Histone modification, a major epigenetic mechanism regulating gene expression through chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancer, including prostate, lung and endometrial cancer (EC). Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. The antitumor effects of PRMT6 inhibition and the role of PRMT6 in EC were investigated, using epigenome multi‑omics analysis, including an assay for chromatin immunoprecipitation sequencing (ChIP‑seq) and RNA sequencing (RNA‑seq). The expression of PRMT6 in EC was analyzed using reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. The effects of PRMT6‑knockdown (KD) were investigated using cell viability and apoptosis assays, as well as its effects on the epigenome, using ChIP‑seq of H3K27ac antibodies and RNA‑seq. Finally, the downstream targets identified by multi‑omics analysis were evaluated. PRMT6 was overexpressed in EC and associated with a poor prognosis. PRMT6‑KD induced histone hypomethylation, while suppressing cell growth and apoptosis. ChIP‑seq revealed that PRMT6 regulated genomic regions related to interferons and apoptosis through histone modifications. The RNA‑seq data demonstrated altered interferon‑related pathways and increased expression of tumor suppressor genes, including NK6 homeobox 1 and phosphoinositide‑3‑kinase regulatory subunit 1, following PRMT6‑KD. RT‑qPCR revealed that eight ERV genes which activated interferon signaling were upregulated by PRMT6‑KD. The data of the present study suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target, to the best of our knowledge, in EC.

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