Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer
Targeting MYC as a Therapeutic Intervention for Anaplastic Thyroid Cancer
复制标题
DOI：
10.1210/jc.2016-3771
复制
发表时间：
2017-07-01
影响因子：
5.8
通讯作者：
Cheng, Sheue-yann
中科院分区：
文献类型：
--
作者：
Enomoto, Keisuke;Zhu, Xuguang;Cheng, Sheue-yann
背景：最近的研究表明，MYC基因的转录是由溴域和外域（BET）蛋白与染色质上的乙酰化组蛋白相互作用驱动的。JQ1是一种有效破坏BET蛋白与乙酰化组蛋白相互作用的有效抑制剂，优先抑制MYC基因的转录。我们最近报道了JQ1通过靶向MYC转录降低甲状腺肿瘤生长并提高小鼠间变性甲状腺癌（ATC）模型的生存率。MYC在人类ATC中的作用以及JQ1是否能有效靶向MYC作为一种治疗方式尚不清楚。目的：研究JQ1在人ATC细胞系和异种移植模型中的作用，了解其潜在的分子机制。设计：我们确定JQ1对细胞系和异种移植物肿瘤的增殖和侵袭的影响。我们确定了jq1影响肿瘤细胞增殖和侵袭的关键调控因子。结果：JQ1通过抑制MYC和上调p21和p27，降低磷酸化Rb，延缓细胞周期从G0/G1期向S期的进展，显著抑制4种ATC细胞系的增殖。JQ1通过减弱上皮-间质转化信号来阻断细胞侵袭。这些基于细胞的研究在异种移植研究中得到进一步证实，JQ1通过抑制p21-cyclin/cyclin依赖性激酶rb - e2f信号传导来抑制肿瘤的大小和生长速度。结论：这些结果表明靶向MYC蛋白可能是人类ATC的一种潜在治疗方式，有效的治疗方案有限。
Context: Recent studies showed that transcription of the MYC gene is driven by the interaction of bromodomain and extraterminal domain (BET) proteins with acetylated histones on chromatin. JQ1, a potent inhibitor that effectively disrupts the interaction of BET proteins with acetylated histones, preferentially suppresses transcription of the MYC gene. We recently reported that JQ1 decreased thyroid tumor growth and improved survival in a mouse model of anaplastic thyroid cancer (ATC) by targeting MYC transcription. The role of MYC in human ATC and whether JQ1 can effectively target MYC as a treatment modality have not been elucidated.Objective: To understand the underlying molecular mechanisms of JQ1, we evaluated its efficacy in human ATC cell lines and xenograft models.Design: We determined the effects of JQ1 on proliferation and invasion in cell lines and xenograft tumors. We identified key regulators critical for JQ1-affected proliferation and invasion of tumor cells.Results: JQ1 markedly inhibited proliferation of four ATC cell lines by suppression of MYC and elevation of p21 and p27 to decrease phosphorylated Rb and delay cell cycle progression from the G0/G1 phase to the S phase. JQ1 blocked cell invasion by attenuating epithelial-mesenchymal transition signals. These cell-based studies were further confirmed in xenograft studies in which the size and rate of tumor growth were inhibited by JQ1 via inhibition of p21-cyclin/cyclin-dependent kinase-Rb-E2F signaling.Conclusions: These results suggest targeting of the MYC protein could be a potential treatment modality for human ATC for which effective treatment options are limited.