BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.
BRD4 as a therapeutic target for nonfunctioning and growth hormone pituitary adenoma.
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BRD4 作为无功能和生长激素垂体腺瘤的治疗靶点
DOI：
10.1093/neuonc/noaa084
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发表时间：
2020-08-17
期刊：
影响因子：
15.9
通讯作者：
Zhao Y
中科院分区：
文献类型：
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作者：
Shi C;Ye Z;Han J;Ye X;Lu W;Ji C;Li Z;Ma Z;Zhang Q;Zhang Y;He W;Chen Z;Cao X;Shou X;Zhou X;Wang Y;Zhang Z;Li Y;Ye H;He M;Chen H;Cheng H;Sun J;Cai J;Huang C;Ye F;Luo C;Zhou B;Ding H;Zhao Y
无功能垂体腺瘤（NFPA）和生长激素垂体腺瘤（GHPA）是垂体腺瘤的两个主要亚型。主要的治疗方法是手术切除。然而，根治性切除仍然具有挑战性，并且几乎没有有效的药物治疗。因此，寻找新的治疗靶点迫在眉睫。含溴结构域蛋白4（BRD 4）是一种表观遗传调节因子，可导致癌基因的异常转录激活。在此，我们研究了BRD 4的病理作用，并评估了BRD 4抑制剂在治疗NFPA和GHPA中的有效性。方法检测BRD 4在NFPA、GHPA及正常垂体组织中的表达。在GH 3和MMQ细胞系、患者来源的肿瘤细胞和PA的体内小鼠异种移植模型中评价了BRD 4抑制剂的功效。进行标准蛋白质印迹、实时PCR和流式细胞术实验以研究BRD 4抑制剂对细胞周期进程、凋亡和下游基因表达模式的影响。结果免疫组化结果显示BRD 4在NFPA和GHPA中呈高表达。体外和体内研究表明，用BRD 4抑制剂ZBC-260处理显著抑制PA细胞的增殖。进一步的机制研究表明，ZBC-260可以下调c-Myc，B细胞淋巴瘤2（Bcl 2）和相关基因的表达，这些基因是垂体肿瘤发生的重要因素。结论在本研究中，我们检测了BRD 4在NFPA和GHPA中的过表达，并评估了BRD 4抑制剂对PA细胞的影响。我们的研究结果表明，BRD 4是NFPA和GHPA的一个有前途的治疗靶点。
Abstract Background Nonfunctioning pituitary adenoma (NFPA) and growth hormone pituitary adenoma (GHPA) are major subtypes of pituitary adenomas (PAs). The primary treatment is surgical resection. However, radical excision remains challenging, and few effective medical therapies are available. It is urgent to find novel targets for the treatment. Bromodomain-containing protein 4 (BRD4) is an epigenetic regulator that leads to aberrant transcriptional activation of oncogenes. Herein, we investigated the pathological role of BRD4 and evaluated the effectiveness of BRD4 inhibitors in the treatment of NFPA and GHPA. Methods The expression of BRD4 was detected in NFPA, GHPA, and normal pituitary tissues. The efficacies of BRD4 inhibitors were evaluated in GH3 and MMQ cell lines, patient-derived tumor cells, and in vivo mouse xenograft models of PA. Standard western blots, real-time PCR, and flow cytometry experiments were performed to investigate the effect of BRD4 inhibitors on cell cycle progression, apoptosis, and the expression patterns of downstream genes. Results Immunohistochemistry studies demonstrated the overexpression of BRD4 in NFPA and GHPA. In vitro and in vivo studies showed that treatment with the BRD4 inhibitor ZBC-260 significantly inhibited the proliferation of PA cells. Further mechanistic studies revealed that ZBC-260 could downregulate the expression of c-Myc, B-cell lymphoma 2 (Bcl2), and related genes, which are vital factors in pituitary tumorigenesis. Conclusion In this study, we determined the overexpression of BRD4 in NFPA and GHPA and assessed the effects of BRD4 inhibitors on PA cells in vitro and in vivo. Our findings suggest that BRD4 is a promising therapeutic target for NFPA and GHPA.
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影响因子：
37.3
作者：
Donati B;Lorenzini E;Ciarrocchi A
通讯作者：
Ciarrocchi A
DOI：
10.1158/1078-0432.ccr-12-3066
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Cheng Z;Gong Y;Ma Y;Lu K;Lu X;Pierce LA;Thompson RC;Muller S;Knapp S;Wang J
通讯作者：
Wang J
影响因子：
12.4
作者：
Bernal, J. A.;Roche, M.;Pintor-Toro, J. A.
通讯作者：
Pintor-Toro, J. A.
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影响因子：
64.8
作者：
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库欣病中反复出现功能获得性 USP8 突变。
影响因子：
44.1
作者：
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