Igarashi Yosuke, Akiyama Yoshimitsu, Shimada Shu, Watanabe Shuichi, Hatano Megumi, Kodera Keita, Okazaki Kohei, Tanji Yoshiaki, Tsukihara Shu, Taniai Tomohiko, Nara Atsushi, Yamane Masahiro, Kamachi Atsushi, Umemura Kentaro, Yasukawa Koya, Ono Hiroaki, Akahoshi Keiichi, Tanabe Minoru, Haruki Koichiro, Furukawa Kenei, Ikegami Toru, Tanaka Shinji
Department of Molecular Oncology, Graduate School of Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
Department of Surgery, The Jikei University School of Medicine, Tokyo, Japan.
JHEP Rep. 2024 Dec 18;7(3):101307. doi: 10.1016/j.jhepr.2024.101307. eCollection 2025 Mar.
BACKGROUND & AIMS: The inhibition of epigenetic regulators activates endogenous retrovirus (ERV) expression, which can stimulate a viral mimicry response in cancer cells. ERV elements are aberrantly expressed in hepatocellular carcinoma (HCC); however, the expression of ERVs regulated by histone modifications and their clinical significance in HCC remain unclear. Here, we identified specific human endogenous retrovirus (HERV) elements epigenetically suppressed by the histone methyltransferase SETDB1 in HCC.
The Cancer Genome Atlas (TCGA) dataset was analyzed to identify HERV elements based on expression levels. knockdown (KD) was performed in mouse and human HCC cells to investigate the resulting biological effects and changes in HERV expression, both and .
TCGA analysis revealed an inverse correlation between and retroelements in human HCC (R = -0.723, = 2.297 × 10), identifying four specific HERV elements in -high expressing HCC cases. Low expression of these four HERVs was associated with poor prognosis, and their combined expression provided additional prognostic insight ( <0.001). Increased expression of the four HERV elements and decreased H3K9me3 levels at these regions were detected in human HCC cells with -KD. In murine HCC cells, -KD impaired tumor growth with increasing CD8-positive T-cell infiltration. Moreover, the interferon α response pathway and multiple ERV elements were activated in mouse HCC cells with -KD. The expression of interferon-stimulated genes, as indicators of a viral mimicry response, was elevated in both murine and human -KD HCC cells.
The suppression of four novel HERV elements by SETDB1 serves as a prognostic marker in HCC. Activation of these SETDB1-regulated HERVs could represent a promising therapeutic strategy for HCC.
An inverse relationship between retroelements including human endogenous retrovirus (HERV) elements and expression was observed in human hepatocellular carcinoma (HCC) by The Cancer Genome Atlas data analysis. We identified four HERV elements downregulated by SETDB1-dependent H3K9me3 in HCC cells, with low expression levels of these HERV elements correlating with poor prognosis in patients with HCC. depletion resulted in upregulation of various interferon-stimulated genes associated with viral mimicry in HCC cells. These findings suggest that the four SETDB1-regulated HERVs could serve as prognostic markers and potential therapeutic targets for HCC.
表观遗传调节因子的抑制会激活内源性逆转录病毒（ERV）的表达，这可刺激癌细胞中的病毒模拟反应。ERV元件在肝细胞癌（HCC）中异常表达；然而，受组蛋白修饰调控的ERVs在HCC中的表达及其临床意义仍不清楚。在此，我们鉴定了在HCC中被组蛋白甲基转移酶SETDB1表观遗传抑制的特定人类内源性逆转录病毒（HERV）元件。
分析癌症基因组图谱（TCGA）数据集，根据表达水平鉴定HERV元件。在小鼠和人类HCC细胞中进行敲低（KD），以研究由此产生的生物学效应以及HERV表达的变化，包括体内和体外。
TCGA分析揭示了人类HCC中SETDB1与逆转录元件之间呈负相关（R = -0.723，P = 2.297×10⁻¹⁰），在SETDB1高表达的HCC病例中鉴定出四个特定的HERV元件。这四个HERV的低表达与预后不良相关，它们的联合表达提供了额外的预后信息（P<0.001）。在SETDB1敲低的人类HCC细胞中检测到这四个HERV元件的表达增加以及这些区域H3K9me3水平降低。在小鼠HCC细胞中，SETDB1敲低会损害肿瘤生长，同时CD8阳性T细胞浸润增加。此外，在SETDB1敲低的小鼠HCC细胞中，干扰素α反应途径和多个ERV元件被激活。作为病毒模拟反应指标的干扰素刺激基因的表达在小鼠和人类SETDB1敲低的HCC细胞中均升高。
SETDB1对四个新型HERV元件的抑制可作为HCC的预后标志物。激活这些受SETDB1调控的HERV可能代表一种有前景的HCC治疗策略。
通过癌症基因组图谱数据分析，在人类肝细胞癌（HCC）中观察到包括人类内源性逆转录病毒（HERV）元件在内的逆转录元件与SETDB1表达之间呈负相关。我们在HCC细胞中鉴定出四个受SETDB依赖的H3K9me3下调的HERV元件，这些HERV元件的低表达水平与HCC患者的不良预后相关。SETDB1缺失导致HCC细胞中与病毒模拟相关的各种干扰素刺激基因上调。这些发现表明，这四个受SETDB1调控的HERV可作为HCC的预后标志物和潜在治疗靶点。
