Hassanie Haifa, Penteado André Berndt, de Almeida Larissa Costa, Calil Raisa Ludmila, da Silva Emery Flávio, Costa-Lotufo Leticia Veras, Trossini Gustavo Henrique Goulart
School of Pharmaceutical Sciences, University of São Paulo Brazil
Institute of Biomedical Sciences, University of São Paulo Brazil.
RSC Med Chem. 2024 Mar 19;15(5):1424-1451. doi: 10.1039/d3md00366c. eCollection 2024 May 22.
Genome stability is governed by chromatin structural dynamics, which modify DNA accessibility under the influence of intra- and inter-nucleosomal contacts, histone post-translational modifications (PTMs) and variations, besides the activity of ATP-dependent chromatin remodelers. These are the main ways by which chromatin dynamics are regulated and connected to nuclear processes, which when dysregulated can frequently be associated with most malignancies. Recently, functional crosstalk between histone modifications and chromatin remodeling has emerged as a critical regulatory method of transcriptional regulation during cell destiny choice. Therefore, improving therapeutic outcomes for patients by focusing on epigenetic targets dysregulated in malignancies should help prevent cancer cells from developing resistance to anticancer treatments. For this reason, SET domain bifurcated histone lysine methyltransferase 1 (SETDB1) has gained a lot of attention recently as a cancer target. SETDB1 is a histone lysine methyltransferase that plays an important role in marking euchromatic and heterochromatic regions. Hence, it promotes the silencing of tumor suppressor genes and contributes to carcinogenesis. Some studies revealed that SETDB1 was overexpressed in various human cancer types, which enhanced tumor growth and metastasis. Thus, SETDB1 appears to be an attractive epigenetic target for new cancer treatments. In this review, we have discussed the effects of its overexpression on the progression of tumors and the development of inhibitor drugs that specifically target this enzyme.
基因组稳定性受染色质结构动力学调控，在核小体内部和之间的接触、组蛋白翻译后修饰（PTMs）及变异的影响下，染色质结构动力学可改变DNA的可及性，此外还受ATP依赖的染色质重塑因子活性的影响。这些是调控染色质动力学并将其与核过程相联系的主要方式，当这些调控失调时，常与大多数恶性肿瘤相关。最近，组蛋白修饰与染色质重塑之间的功能串扰已成为细胞命运选择过程中转录调控的关键调节方法。因此，通过关注恶性肿瘤中失调的表观遗传靶点来改善患者的治疗效果，应有助于防止癌细胞对抗癌治疗产生耐药性。出于这个原因，SET结构域分叉组蛋白赖氨酸甲基转移酶1（SETDB1）作为一个癌症靶点最近受到了广泛关注。SETDB1是一种组蛋白赖氨酸甲基转移酶，在标记常染色质和异染色质区域中起重要作用。因此，它促进肿瘤抑制基因的沉默并有助于致癌作用。一些研究表明，SETDB1在多种人类癌症类型中过表达，这增强了肿瘤的生长和转移。因此，SETDB1似乎是新型癌症治疗中一个有吸引力的表观遗传靶点。在这篇综述中，我们讨论了其过表达对肿瘤进展的影响以及特异性靶向该酶的抑制剂药物的研发情况。
