BRD9 Inhibition by Natural Polyphenols Targets DNA Damage/Repair and Apoptosis in Human Colon Cancer Cells.
BRD9 Inhibition by Natural Polyphenols Targets DNA Damage/Repair and Apoptosis in Human Colon Cancer Cells.
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DOI：
10.3390/nu14204317
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发表时间：
2022-10-15
期刊：
影响因子：
5.9
通讯作者：
Dashwood, Roderick Hugh
中科院分区：
文献类型：
--
作者：
Kapoor, Sabeeta;Damiani, Elisabetta;Wang, Shan;Dharmanand, Ravirajan;Tripathi, Chakrapani;Perez, Jorge Enrique Tovar;Dashwood, Wan Mohaiza;Rajendran, Praveen;Dashwood, Roderick Hugh
表观遗传机制在结直肠癌(CRC)和其他恶性肿瘤的病因学中起着重要作用，部分原因是溴域(BRD)功能失调。溴域和端外(BET)家族的抑制剂已经作为抗癌药物进入临床试验，人们对其他乙酰基‘阅读器’蛋白作为治疗靶点的兴趣也在增长，包括非BET成员溴域包含蛋白9(BRD9)。我们在此报道，BRD9的过度表达与结直肠癌患者的不良预后有关，并且siRNA介导的BRD9基因敲除降低了人结肠癌细胞的细胞活力和激活了细胞凋亡，这与DNA损伤的增加是一致的。寻找天然化合物作为BRD9拮抗剂，在电子计算机上进行分子对接，确定了几种多酚，如表没食子儿茶素没食子酸酯(EGCG)、Equol、Qercetin和Aspalathin，它们具有良好的结合能，并得到BROMOScan®(DiscoverX)和等温滴定量热法实验的支持。多酚类化合物类似于BRD9基因敲除和iBRD9处理，在降低结肠癌细胞存活率、抑制集落形成、促进DNA损伤和凋亡方面具有相似的作用。正常的结肠上皮细胞没有受到影响，这意味着癌症特异性的影响。这些发现表明，天然多酚识别并靶向抑制BRD9，可能在临床环境中作为有用的溴域疗法的先导化合物。
Epigenetic mechanisms play an important role in the etiology of colorectal cancer (CRC) and other malignancies due, in part, to deregulated bromodomain (BRD) functions. Inhibitors of the bromodomain and extraterminal (BET) family have entered into clinical trials as anticancer agents, and interest has grown in other acetyl ‘reader’ proteins as therapeutic targets, including non-BET member bromodomain-containing protein 9 (BRD9). We report here that overexpression of BRD9 is associated with poor prognosis in CRC patients, and that siRNA-mediated knockdown of BRD9 decreased cell viability and activated apoptosis in human colon cancer cells, coincident with increased DNA damage. Seeking natural compounds as BRD9 antagonists, molecular docking in silico identified several polyphenols such as Epigallocatechin-3-gallate (EGCG), Equol, Quercetin, and Aspalathin, with favorable binding energies, supported by BROMOscan® (DiscoverX) and isothermal titration calorimetry experiments. Polyphenols mimicked BRD9 knockdown and iBRD9 treatment in reducing colon cancer cell viability, inhibiting colony formation, and enhancing DNA damage and apoptosis. Normal colonic epithelial cells were unaffected, signifying cancer-specific effects. These findings suggest that natural polyphenols recognize and target BRD9 for inhibition, and might serve as useful lead compounds for bromodomain therapeutics in the clinical setting.
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DOI：
10.1007/978-1-4939-6740-7_16
发表时间：
2017-01-01
期刊：
PROTEOME BIOINFORMATICS
影响因子：
--
作者：
Paxman, Jason J.;Heras, Begona
通讯作者：
Heras, Begona
影响因子：
3.5
作者：
Campos, Catarina;Fragoso, Sofia;Pojo, Marta
通讯作者：
Pojo, Marta
影响因子：
5.9
作者：
Dutra, Luiz Antonio;Heidenreich, David;dos Santos, Jean Leandro
通讯作者：
dos Santos, Jean Leandro
影响因子：
2.5
作者：
Damiani E;Duran MN;Mohan N;Rajendran P;Dashwood RH
通讯作者：
Dashwood RH
影响因子：
5.2
作者：
Bell, Catherine M.;Raffeiner, Philipp;Vogt, Peter K.
通讯作者：
Vogt, Peter K.