<br>SETDB1：癌症治疗潜力和抑制剂研究的进展和展望,Bioorganic Chemistry

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SETDB1：癌症治疗潜力和抑制剂研究的进展和展望
Bioorganic Chemistry ( IF 4.5 ) Pub Date : 2024-02-17 , DOI: 10.1016/j.bioorg.2024.107219
Tingnan Ma ₁ , Feifei Xu ₂ , Yingying Hou ₁ , Yongquan Shu ₁ , Zhipeng Zhao ₁ , Yaru Zhang ₁ , Lan Bai ₁ , Lu Feng ₃ , Lei Zhong ₁

Affiliation

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 的二甲基化和三甲基化。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，在肿瘤发生和进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耐药的背景下尤为明显。此外，SETDB1 失调与各种类型肿瘤的不良预后之间存在很强的关联。SETDB1 的致癌作用主要来自其甲基转移酶功能，这有助于建立浓缩且转录无活性的异染色质状态。这导致通常阻碍癌症发展的基因失活和可能触发免疫反应的反转录转座子沉默。这些发现强调了 SETDB1 作为抗肿瘤治疗靶点的巨大潜力。然而，尽管近年来肿瘤生物学研究取得了重大进展，但 SETDB1 靶向治疗仍然存在挑战。为了更好地促进靶向 SETDB1 的抗肿瘤疗法的开发，我们在此帐户中对 SETDB1 进行了全面综述。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，我们讨论了遇到的挑战，并为 SETDB1 靶向抗肿瘤治疗的发展提供了前景。

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SETDB1: Progress and prospects in cancer treatment potential and inhibitor research

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.

更新日期：2024-02-17

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