Zhao Zhipeng, Feng Lu, Peng Xuerun, Ma Tingnan, Tong Rongsheng, Zhong Lei
Department of Pharmacy, Personalized Drug Therapy Key Laboratory of Sichuan Province, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, China.
Department of Emergency, Sichuan Academy of Medical Sciences & Sichuan Provincial People's Hospital, Chengdu, China.
Front Pharmacol. 2022 Dec 13;13:1073713. doi: 10.3389/fphar.2022.1073713. eCollection 2022.
Epigenetic alterations are implicated in tumour immune evasion and immune checkpoint blockade (ICB) resistance. SET domain bifurcated histone methyltransferase 1 (SETDB1) is a histone lysine methyltransferase that catalyses histone H3K9 di- and tri-methylation on euchromatin, and growing evidence indicates that SETDB1 amplification and abnormal activation are significantly correlated with the unfavourable prognosis of multiple malignant tumours and contribute to tumourigenesis and progression, immune evasion and ICB resistance. The main underlying mechanism is H3K9me3 deposition by SETDB1 on tumour-suppressive genes, retrotransposons, and immune genes. SETDB1 targeting is a promising approach to cancer therapy, particularly immunotherapy, because of its regulatory effects on endogenous retroviruses. However, SETDB1-targeted therapy remains challenging due to potential side effects and the lack of antagonists with high selectivity and potency. Here, we review the role of SETDB1 in tumourigenesis and immune regulation and present the current challenges and future perspectives of SETDB1 targeted therapy.
表观遗传改变与肿瘤免疫逃逸和免疫检查点阻断（ICB）耐药有关。SET结构域分叉组蛋白甲基转移酶1（SETDB1）是一种组蛋白赖氨酸甲基转移酶，可催化常染色质上的组蛋白H3K9二甲基化和三甲基化，越来越多的证据表明，SETDB1扩增和异常激活与多种恶性肿瘤的不良预后显著相关，并促进肿瘤发生和进展、免疫逃逸和ICB耐药。主要潜在机制是SETDB1将H3K9me3沉积在肿瘤抑制基因、逆转座子和免疫基因上。由于SETDB1对内源性逆转录病毒的调节作用，靶向SETDB1是一种很有前景的癌症治疗方法，尤其是免疫治疗。然而，由于潜在的副作用以及缺乏高选择性和高效能的拮抗剂，靶向SETDB1的治疗仍然具有挑战性。在这里，我们综述了SETDB1在肿瘤发生和免疫调节中的作用，并介绍了靶向SETDB1治疗的当前挑战和未来前景。
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