Division of Systems Virology, Department of Infectious Disease Control, International Research Center for Infectious Diseases, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 1088639, Japan.
Laboratory of Systems Virology, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 6068507, Japan.
Sci Adv. 2020 Oct 21;6(43). doi: 10.1126/sciadv.abc3020. Print 2020 Oct.
Gene expression aberration is a hallmark of cancers, but the mechanisms underlying such aberrations remain unclear. Human endogenous retroviruses (HERVs) are genomic repetitive elements that potentially function as enhancers. Since numerous HERVs are epigenetically activated in tumors, their activation could cause global gene expression aberrations in tumors. Here, we show that HERV activation in tumors leads to the up-regulation of hundreds of transcriptional suppressors, namely, Krüppel-associated box domain-containing zinc-finger family proteins (KZFPs). KZFP genes are preferentially encoded nearby the activated HERVs in tumors and transcriptionally regulated by these adjacent HERVs. Increased HERV and KZFP expression in tumors was associated with better disease conditions. Increased KZFP expression in cancer cells altered the expression of genes related to the cell cycle and cell-matrix adhesion and suppressed cellular growth, migration, and invasion abilities. Our data suggest that HERV activation in tumors drives the synchronized elevation of KZFP expression, presumably leading to tumor suppression.
基因表达失常是癌症的一个标志，但这种失常的机制尚不清楚。人类内源性逆转录病毒（HERV）是基因组中的重复元件，可能具有增强子的功能。由于大量的 HERV 在肿瘤中被表观遗传激活，它们的激活可能导致肿瘤中全局基因表达失常。在这里，我们表明肿瘤中的 HERV 激活导致数百个转录抑制剂的上调，即 KRÜPPEL 相关盒域包含锌指家族蛋白（KZFPs）。KZFP 基因在肿瘤中优先被邻近激活的 HERV 编码，并受这些邻近 HERV 的转录调控。肿瘤中 HERV 和 KZFP 的表达增加与更好的疾病状况相关。癌细胞中 KZFP 表达的增加改变了与细胞周期和细胞-基质黏附相关的基因表达，并抑制了细胞的生长、迁移和侵袭能力。我们的数据表明，肿瘤中 HERV 的激活驱动了 KZFP 表达的同步升高，可能导致肿瘤抑制。
