视网膜母细胞瘤(RB)是儿童常见的恶性肿瘤。尽管RB1基因突变是RB的知名病因，但MYCN基因扩增也可导致该疾病，且为不良预后因素。在各种肿瘤类型的研究中，已证明MYCN抑制是一种有效阻止肿瘤生长的方法。出于直接靶向MYCN的困难，已经发展了各种间接方法来克服这一难题，如调节MYCN上游的超强增强子（SE）。该研究使用的用于治疗MYCN扩增的RB的药物是THZ1，一种CDK7抑制剂，它通过干扰SE的活性有效抑制转录过程。研究结果在体外和体内实验中确认了THZ1对RB的抗癌活性。根据RNA测序分析，THZ1治疗会影响RB中的多个基因。此外，THZ1治疗引起的基因表达变化富集在核糖体、内吞作用、细胞周期和凋亡等方面。此外，ChIP-Seq和RNA-seq数据的联合分析结果暗示了SE在调控MYCN、OTX2和SOX4等关键转录因子表达中的潜在作用。此外，还进行了ChIP-qPCR实验证实了MYCN和SE之间的相互作用。总之，THZ1引起了RB中基因转录的显著改变，从而抑制了细胞增殖，干扰了细胞周期，并增加了细胞凋亡。THZ1的疗效与MYCN扩增程度正相关，并可能通过干扰上游SEs来发挥作用。版权所有©2023由Elsevier B.V.出版。

Retinoblastoma (RB) is a common malignancy that primarily affects pediatric populations. Although a well-known cause of RB is RB1 mutation, MYCN amplification can also lead to the disease, which is a poor prognosis factor. Studies conducted in various tumor types have shown that MYCN inhibition is an effective approach to impede tumor growth. Various indirect approaches have been developed to overcome the difficulty of directly targeting MYCN, such as modulating the super enhancer (SE) upstream of MYCN. The drug used in this study to treat MYCN-amplified RB was THZ1, a CDK7 inhibitor that can effectively suppress transcription by interfering with the activity of SEs. The study findings confirmed the anticancer activity of THZ1 against RB in both in vitro and in vivo experiments. Therapy with THZ1 was found to affect numerous genes in RB according to the RNA-seq analysis. Moreover, the gene expression changes induced by THZ1 treatment were enriched in ribosome, endocytosis, cell cycle, apoptosis, etc. Furthermore, the combined analysis of ChIP-Seq and RNA-seq data suggested a potential role of SEs in regulating the expression of critical transcription factors, such as MYCN, OTX2, and SOX4. Moreover, ChIP-qPCR experiments were conducted to confirm the interaction between MYCN and SEs. In conclusion, THZ1 caused substantial changes in gene transcription in RB, resulting in inhibited cell proliferation, interference with the cell cycle, and increased apoptosis. The efficacy of THZ1 is positively correlated with the degree of MYCN amplification and is likely exerted by interfering with MYCN upstream SEs.Copyright © 2023. Published by Elsevier B.V.