Abstract：
SET domain bifurcated methyltransferase 1 (SETDB1) serves as a histone lysine methyltransferase, catalyzing the di- and tri-methylation of histone H3K9. Mounting evidence indicates that the abnormal expression or activity of SETDB1, either through amplification or mutation, plays a crucial role in tumorigenesis and progression. This is particularly evident in the context of tumor immune evasion and resistance to immune checkpoint blockade therapy. Furthermore, there is a robust association between SETDB1 dysregulation and an unfavorable prognosis across various types of tumors. The oncogenic role of SETDB1 primarily arises from its methyltransferase function, which contributes to the establishment of a condensed and transcriptionally inactive heterochromatin state. This results in the inactivation of genes that typically hinder cancer development and silencing of retrotransposons that could potentially trigger an immune response. These findings underscore the substantial potential for SETDB1 as an anti-tumor therapeutic target. Nevertheless, despite significant strides in recent years in tumor biology research, challenges persist in SETDB1-targeted therapy. To better facilitate the development of anti-tumor therapy targeting SETDB1, we have conducted a comprehensive review of SETDB1 in this account. We present the structure and function of SETDB1, its role in various tumors and immune regulation, as well as the advancements made in SETDB1 antagonists. Furthermore, we discuss the challenges encountered and provide perspectives for the development of SETDB1-targeted anti-tumor therapy.
摘要：
SET结构域分叉甲基转移酶1（SETDB1）作为组蛋白赖氨酸甲基转移酶，催化组蛋白H3K9的二-和三-甲基化。越来越多的证据表明，SETDB1的异常表达或活性，无论是通过扩增还是突变，在肿瘤发生和发展中起着至关重要的作用。这在肿瘤免疫逃避和对免疫检查点阻断疗法的抗性的背景下尤其明显。此外，在各种类型的肿瘤中,SETDB1失调与不良预后之间存在密切关联.SETDB1的致癌作用主要来自其甲基转移酶功能，这有助于建立凝聚和转录失活的异染色质状态。这导致通常阻碍癌症发展的基因失活和可能潜在地触发免疫应答的反转录转座子沉默。这些发现强调了SETDB1作为抗肿瘤治疗靶标的巨大潜力。然而，尽管近年来肿瘤生物学研究取得了重大进展，SETDB1靶向治疗仍然存在挑战.为了更好地促进针对SETDB1的抗肿瘤治疗的发展，我们在这方面对SETDB1进行了全面的综述。我们介绍了SETDB1的结构和功能，它在各种肿瘤和免疫调节中的作用，以及SETDB1拮抗剂的进展。此外，我们讨论了所遇到的挑战,并为SETDB1靶向抗肿瘤治疗的发展提供了前景.
