Chang Yu-Hsuan, Goyama Susumu
Division of Molecular Oncology, Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo, Japan.
Cancer Sci. 2025 Sep;116(9):2331-2339. doi: 10.1111/cas.70116. Epub 2025 Jun 4.
SET domain bifurcated histone methyltransferase 1 (SETDB1) is a histone H3 lysine 9 (H3K9) methyltransferase, functioning in transcriptional silencing of the transposable elements (TEs), endogenous retroviruses (ERVs), interferon-stimulated genes (ISGs), and immune cell-related molecules. SETDB1 collaborates with cofactors such as ATF7IP and TRIM28 and functions in concert with DNA methylation to maintain gene repression in both stem cells and differentiated somatic cells. Given its gene targets, recent studies have shown that SETDB1 is a critical immune checkpoint gene in both solid and hematological tumors. In this review, we first discuss the role of SETDB1 in gene regulation through its histone methyltransferase activity, including an overview of its structural features and key cofactors. We then highlight the lineage-specific roles of SETDB1 in both normal hematopoietic processes and hematological malignancies, emphasizing its function as an immune checkpoint molecule that suppresses natural killer (NK) cell-mediated antileukemia responses.
SET结构域双叉组蛋白甲基转移酶1（SETDB1）是一种组蛋白H3赖氨酸9（H3K9）甲基转移酶，在转座元件（TEs）、内源性逆转录病毒（ERVs）、干扰素刺激基因（ISGs）和免疫细胞相关分子的转录沉默中发挥作用。SETDB1与诸如ATF7IP和TRIM28等辅因子协作，并与DNA甲基化协同作用，以维持干细胞和分化体细胞中的基因抑制。鉴于其基因靶点，最近的研究表明，SETDB1在实体瘤和血液肿瘤中都是关键的免疫检查点基因。在本综述中，我们首先讨论SETDB1通过其组蛋白甲基转移酶活性在基因调控中的作用，包括其结构特征和关键辅因子的概述。然后，我们强调SETDB1在正常造血过程和血液恶性肿瘤中的谱系特异性作用，重点阐述其作为抑制自然杀伤（NK）细胞介导的抗白血病反应的免疫检查点分子的功能。
