BET bromodomain proteins are required for glioblastoma cell proliferation.
BET bromodomain proteins are required for glioblastoma cell proliferation.
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DOI：
10.4161/epi.27906
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发表时间：
2014-04
期刊：
影响因子：
3.7
通讯作者：
Ayad NG
中科院分区：
文献类型：
--
作者：
Pastori C;Daniel M;Penas C;Volmar CH;Johnstone AL;Brothers SP;Graham RM;Allen B;Sarkaria JN;Komotar RJ;Wahlestedt C;Ayad NG
表观遗传蛋白最近成为新的抗癌靶点。其中，布罗莫结构域和额外的末端结构域（BET）蛋白识别赖氨酸乙酰化组蛋白，从而调节基因表达。新描述的抑制BET蛋白BRD 2、BRD 3和BRD 4的小分子在体外和体内减少NUT（睾丸中的核蛋白）-中线癌、多发性骨髓瘤和白血病细胞的增殖。这些发现促使我们确定BET蛋白是否可以作为最常见的原发性成人脑肿瘤胶质母细胞瘤（GBM）的治疗靶点。我们对GBM肿瘤样品和对照进行了NanoString分析，以鉴定新的治疗靶点。使用GBM细胞系和干细胞的几种细胞增殖测定来分析药物I-BET 151相对于替莫唑胺（TMZ）或细胞周期抑制剂的功效。最后，我们进行异种移植实验以确定I-BET 151在体内的功效。我们证明BRD 2和BRD 4 RNA在GBM中显着过表达，这表明BET蛋白抑制可能是减少GBM细胞增殖的有效手段。在胶质母细胞瘤细胞中破坏BRD 4表达减少细胞周期进程。类似地，用BET蛋白抑制剂I-BET 151处理在体外和体内减少GBM细胞增殖。I-BET 151处理在G1/S细胞周期转换时富集细胞。重要的是，I-BET 151在抑制GBM细胞增殖方面与TMZ（目前给予GBM患者的化疗治疗）一样有效。由于I-BET 151通过阻止细胞周期进程来抑制GBM细胞增殖，我们提出BET蛋白抑制可能是患有TMZ耐药肿瘤的GBM患者的可行治疗选择。
Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine-acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I-BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I-BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors.