Histone arginine methyltransferase CARM1 selective inhibitor TP-064 induces apoptosis in endometrial cancer

Inoue, Futaba; Sone, Kenbun; Toyohara, Yusuke; Tanimoto, Saki; Takahashi, Yu; Kusakabe, Misako; Kukita, Asako; Honjoh, Harunori; Nishijima, Akira; Taguchi, Ayumi; Miyamoto, Yukio; Iriyama, Takayuki; Uchino, Mayuyo-mori; Tsuruga, Tetsushi; Wada‐Hiraike, Osamu; Oda, Katsutoshi; Osuga, Yutaka

doi:10.1016/j.bbrc.2022.02.086

Cited by 8 publications

(12 citation statements)

References 20 publications

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“…As expected, PRMT and lysine methyltransferase are therapeutic targets for the treatment of various types of cancer, including breast, prostate, lung and blood cancer (18). In a previous study by the authors, it was reported that the expression of PRMT4 [also known as coactivator-associated arginine methyltransferase 1 (CARM1)] was increased in EC, and treatment with a selective inhibitor of CARM1 resulted in the apoptosis-induced suppression of cell proliferation in EC cell lines (19).…”

Section: Introductionmentioning

confidence: 66%

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

Inoue,

Sone,

Kumegawa

et al. 2024

Int J Oncol

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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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Section: Introductionmentioning

confidence: 66%

“…Small interfering RNA (siRNA) transfection. siRNA transfection was performed as previously described (19). Briefly, siRNAs were transfected at 37˚C for 3.5 h using Lipofectamine RNA interference (RNAi)MAX Transfection Reagent (Thermo Fisher Scientific, Inc.), and the final concentration of siRNAs was 100 nM.…”

Section: Methodsmentioning

confidence: 99%

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

Inoue,

Sone,

Kumegawa

et al. 2024

Int J Oncol

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“…Indeed, some recently developed specific and potent CARM1 small-molecule inhibitors have been tested to treat a subset of cancers. 67 , 88 , 89 , 90 , 91 Hopefully they could become approved drugs for cancer treatment in the future.…”

Section: Discussionmentioning

confidence: 99%

Coactivator-associated arginine methyltransferase 1: A versatile player in cell differentiation and development

Lyu

Ning

et al. 2023

Genes & Diseases

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“…Therefore, the clinical application of histone methyltransferase inhibitors has attracted attention as a novel therapeutic strategy for cancers. Our group previously investigated histone methyltransferases and showed its e cacy on gynecological cancers [20][21][22]. Moreover, the e cacy of histone methyltransferases combined with PARP inhibitors has been reported [23,24].…”

Section: Introductionmentioning

confidence: 99%

Synthetic lethality from the combination of a histone methyltransferase, SUV39H2 inhibitor and a poly (ADP-ribose) polymerase inhibitor for uterine leiomyosarcoma

Toyohara,

Sone,

Kumegawa

et al. 2024

Preprint

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Background: Uterine leiomyosarcoma (uLMS) has a poor prognosis owing to its high recurrence rate and resistance to chemotherapy. Therefore, novel therapeutic targets for uLMS need to be discovered. SUV39H2 is a histone methyltransferase that promotes the repair of double-stranded DNA breaks by recruiting phosphorylated H2AX (γH2AX). In this study, we investigated the potential therapeutic targets of SUV39H2 in uLMS and the mechanism of synthetic lethality between PARP inhibitors and SUV39H2 inhibitors, OTS186935. Methods: First, we analyzed the mRNA and protein expression of SUV39H2 in clinical tissues of uLMS, normal myometrium, and leiomyomas using real-time polymerase chain reaction and immunohistochemistry, respectively. Next, we conducted drug sensitivity assays for OTS186935 alone and in combination with olaparib, a poly (ADP-ribose) polymerase inhibitor, using uLMS cell lines, SK-LMS-1 and SK-UT-1. We conducted an annexin assay to investigate the mechanisms of cellular death. We performed Western blotting, immunofluorescence, and chromatin immunoprecipitation sequencing (ChIP-seq) to investigate γH2AX following OTS186935 treatment in addition to in vivo experiments using nude mice with subcutaneously implanted uLMS. Results: SUV39H2 expression was significantly increased in uLMS compared to that in normal myometrium and leiomyomas. OTS186935 decreased cell viability in both cell lines, and its combination with olaparib resulted in synthetic lethality in SK-UT-1 cells (combination index = 0.87). Annexin assay revealed that the combination therapy induced apoptosis. After treatment with OTS186935, γH2AX accumulation decreased. ChIP-seq also showed downregulated γH2AX following OTS186935 treatment. Notably, the combination with OTS186935 and PARP inhibitor was significantly more effective in vivo. Conclusion: OTS186935 inhibits double-stranded DNA break repair as evidenced by γH2AX downregulation through ChIP-seq and other assays. OTS186935 combined with olaparib induces synthetic lethality in patients with uLMS.

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Histone arginine methyltransferase CARM1 selective inhibitor TP-064 induces apoptosis in endometrial cancer

Cited by 8 publications

References 20 publications

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

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

Coactivator-associated arginine methyltransferase 1: A versatile player in cell differentiation and development

Synthetic lethality from the combination of a histone methyltransferase, SUV39H2 inhibitor and a poly (ADP-ribose) polymerase inhibitor for uterine leiomyosarcoma

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