<br>BRD4 抑制剂 dBET57 通过靶向神经母细胞瘤中超级增强子相关基因发挥抗癌作用,Journal of Immunology Research

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BRD4 抑制剂 dBET57 通过靶向神经母细胞瘤中超级增强子相关基因发挥抗癌作用
Journal of Immunology Research ( IF 3.5 ) Pub Date : 2022-11-16 , DOI: 10.1155/2022/7945884
Si-Qi Jia _{1,

2} , Ran Zhuo _{1,

3} , Zi-Mu Zhang ₁ , Yang Yang ₁ , Yan-Fang Tao ₁ , Jian-Wei Wang ₁ , Xiao-Lu Li ₁ , Yi Xie ₁ , Gen Li ₁ , Di Wu ₁ , Yan-Ling Chen ₁ , Juan-Juan Yu ₁ , Chen-Xi Feng ₁ , Zhi-Heng Li ₁ , Rong-Fang Zhou ₁ , Ran-Dong Yang ₁ , Peng-Cheng Yang ₁ , Bi Zhou ₁ , Xiao-Mei Wan ₁ , Yu-Meng Wu ₁ , Wan-Yan Jiao ₁ , Ni-Na Zhou ₁ , Fang Fang ₁ , Jian Pan ₁

Affiliation

神经母细胞瘤（NB）是儿童中最常见的神经嵴细胞来源的实体瘤，高危患者预后较差。研究发现，约 20% 的神经母细胞瘤病例中癌基因 MYCN 的扩增水平极高。近年来，通过靶向蛋白水解嵌合体（PROTAC）技术靶向水解BRD4来间接抑制MYCN转录的研究非常热门。 dBET57（S0137，Selleck，TX，美国）是一种基于 PROTAC 技术的新型有效的异双功能小分子降解剂。本研究的目的是探讨dBET57对NB的治疗作用及其潜在机制。在本研究中，我们发现dBET57可以靶向BRD4泛素化并破坏NB细胞的增殖能力。同时，dBET57还可以诱导细胞凋亡、细胞周期停滞和减少迁移。此外，dBET57在体内异种移植肿瘤模型中也具有很强的抗增殖功能。从机制上来说，dBET57通过与CRBN结合，靶向BET蛋白家族和MYCN蛋白家族，破坏NB细胞的SE景观。结合RNA-seq和ChIP-seq公共数据库分析，我们鉴定了NB中的超级增强子相关基因TBX3和ZMYND8作为dBET57的潜在下游靶标，并通过实验验证它们在NB的发生和发展中发挥重要作用。总之，这些结果表明dBET57可能是治疗NB的有效新治疗药物。

"点击查看英文标题和摘要"

The BRD4 Inhibitor dBET57 Exerts Anticancer Effects by Targeting Superenhancer-Related Genes in Neuroblastoma

Neuroblastoma (NB) is the most common solid tumor of the neural crest cell origin in children and has a poor prognosis in high-risk patients. The oncogene MYCN was found to be amplified at extremely high levels in approximately 20% of neuroblastoma cases. In recent years, research on the targeted hydrolysis of BRD4 to indirectly inhibit the transcription of the MYCN created by proteolysis targeting chimaera (PROTAC) technology has become very popular. dBET57 (S0137, Selleck, TX, USA) is a novel and potent heterobifunctional small molecule degrader based on PROTAC technology. The purpose of this study was to investigate the therapeutic effect of dBET57 in NB and its potential mechanism. In this study, we found that dBET57 can target BRD4 ubiquitination and disrupt the proliferation ability of NB cells. At the same time, dBET57 can also induce apoptosis, cell cycle arrest, and decrease migration. Furthermore, dBET57 also has a strong antiproliferation function in xenograft tumor models in vivo. In terms of mechanism, dBET57 targets the BET protein family and the MYCN protein family by associating with CRBN and destroys the SE landscape of NB cells. Combined with RNA-seq and ChIP-seq public database analysis, we identified the superenhancer-related genes TBX3 and ZMYND8 in NB as potential downstream targets of dBET57 and experimentally verified that they play an important role in the occurrence and development of NB. In conclusion, these results suggest that dBET57 may be an effective new therapeutic drug for the treatment of NB.

更新日期：2022-11-16

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