Inhibition of protein arginine methyltransferase 6 (PRMT6) activates interferon signaling and induces apoptosis in endometrial cancer cells via histone modification [ChIP-seq]
Histone modification, a major epigenetic mechanism which regulates gene expression by chromatin remodeling, introduces dynamic changes in chromatin architecture. Protein arginine methyltransferase 6 (PRMT6) is overexpressed in various types of cancers. Epigenome regulates the expression of endogenous retrovirus (ERV), which activates interferon signaling related to cancer. We investigated the antitumor effects of PRMT6 inhibition and the role of PRMT6 in endometrial cancer (EC), using epigenome multi-omics analysis including assay for chromatin immunoprecipitation sequencing (ChIP-seq) and ribonucleic acid sequencing (RNA-seq). The expression of PRMT6 in EC was analyzed using real-time quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry (IHC). The prognostic impact of PRMT6 expression was evaluated using IHC. We investigated the effects of PRMT6-knockdown (KD) using cell viability and apoptosis assays, as well as its effects on the epigenome using ChIP-seq of H3K27ac antibodies and RNA-seq. Finally, we evaluated the downstream targets identified by multi-omics analysis. 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. RNA-seq data showed altered interferon-related pathways and increased expression of tumor suppressor genes, such as NKX6-1 and PIK3R1, after PRMT6-KD. RT-qPCR showed that eight ERV genes which activated interferon signaling were upregulated by PRMT6-KD. Our data suggested that PRMT6 inhibition induced apoptosis through interferon signaling activated by ERV. PRMT6 regulated tumor suppressor genes and may be a novel therapeutic target in EC. Overall design: PRMT6 knockdown in HEC1B endometrial cancer cell line