The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo.
The bromodomain inhibitor JQ1 triggers growth arrest and apoptosis in testicular germ cell tumours in vitro and in vivo.
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DOI：
10.1111/jcmm.13059
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发表时间：
2017-07
影响因子：
5.3
通讯作者：
Schorle H
中科院分区：
文献类型：
--
作者：
Jostes S;Nettersheim D;Fellermeyer M;Schneider S;Hafezi F;Honecker F;Schumacher V;Geyer M;Kristiansen G;Schorle H
II型睾丸生殖细胞癌（TGCT）是年轻男性（20-40岁）中最常诊断的肿瘤，并被分类为腺瘤或非腺瘤。TGCT通常通过睾丸切除术和化疗或放疗进行治疗。然而，转移性非肿瘤（胚胎癌）的一个子集仅显示不完全缓解或复发，需要新的治疗选择。最近的研究表明，小分子抑制剂JQ 1在肿瘤治疗中的有效应用，干扰了“溴结构域和末端外（BET）”蛋白的功能。JQ 1处理的TGCT细胞系显示指示DNA损伤和细胞应激反应的基因上调，并诱导细胞周期停滞。表现为JQ 1敏感的胚胎癌（EC）细胞系显示多能性因子的下调和中胚层分化的诱导。相比之下，类胶质瘤TCam-2细胞耐受更高的JQ 1浓度，并且对分化具有抗性。体内异种移植的EC显示出对JQ 1的响应，肿瘤大小、增殖率和血管生成减少。最后，与单一疗法相比，JQ 1和组蛋白脱乙酰酶抑制剂罗米地辛的组合允许更低的剂量和更少的频率应用。因此，我们建议JQ 1与罗米地辛组合可以作为（混合）TGCT的新治疗选择。
Type II testicular germ cell cancers (TGCT) are the most frequently diagnosed tumours in young men (20–40 years) and are classified as seminoma or non‐seminoma. TGCTs are commonly treated by orchiectomy and chemo‐ or radiotherapy. However, a subset of metastatic non‐seminomas (embryonal carcinomas) displays only incomplete remission or relapse and requires novel treatment options. Recent studies have shown effective application of the small‐molecule inhibitor JQ1 in tumour therapy, which interferes with the function of ‘bromodomain and extraterminal (BET)’ proteins. JQ1‐treated TGCT cell lines display up‐regulation of genes indicative for DNA damage and cellular stress response and induce cell cycle arrest. Embryonal carcinoma (EC) cell lines, which presented as JQ1 sensitive, display down‐regulation of pluripotency factors and induction of mesodermal differentiation. In contrast, seminoma‐like TCam‐2 cells tolerated higher JQ1 concentrations and were resistant to differentiation. ECs xenografted in vivo showed a reduction in tumour size, proliferation rate and angiogenesis in response to JQ1. Finally, the combination of JQ1 and the histone deacetylase inhibitor romidepsin allowed for lower doses and less frequent application, compared with monotherapy. Thus, we propose that JQ1 in combination with romidepsin may serve as a novel therapeutic option for (mixed) TGCTs.