Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma
Targeting CDK12-mediated transcription regulation in anaplastic thyroid carcinoma
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靶向 CDK12 介导的甲状腺未分化癌转录调控
DOI：
10.1016/j.bbrc.2019.10.052
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发表时间：
2019-12-10
影响因子：
3.1
通讯作者：
Zhang, Lirong
中科院分区：
文献类型：
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作者：
Geng, Meijuan;Yang, Yiyi;Zhang, Lirong
未分化甲状腺癌（ATC）是甲状腺癌中最具侵袭性的类型，目前尚无有效的治疗方法。因此，鉴定新的抗ATC药物迫在眉睫。在本研究中，我们发现ATC细胞对THZ531高度敏感，THZ531是一种有效的转录细胞周期蛋白依赖性激酶（CDK）CDK12抑制剂。基于细胞的实验表明，抑制CDK12可显著阻碍细胞周期进程，诱导细胞凋亡，并损害ATC细胞的集落形成。THZ531导致延伸中的RNA聚合酶II缺失，并抑制ATC细胞中的基因表达。通过对基因表达谱和超级增强子图谱进行综合分析，并结合功能实验，发现了两个新的ATC癌基因，ZC3H4和NEMP1。此外，抑制CDK12可增强ATC细胞对阿霉素介导的化疗的敏感性。因此，这些研究结果表明，CDK12是ATC治疗的一个潜在治疗靶点，对其进行抑制可能有助于克服ATC患者的化疗耐药性。（C）2019爱思唯尔公司。保留所有权利。
Anaplastic thyroid carcinoma (ATC) is the most aggressive type of thyroid cancer, with no effective treatment available. Identification of new anti-ATC drugs represents an urgent need. In this study, we find that ATC cells are highly sensitive to THZ531, a potent inhibitor of the transcriptional cyclin-dependent kinase (CDK), CDK12. Cell-based assays demonstrate that CDK12 inhibition significantly impedes cell cycle progression, induces apoptotic cell death, and impairs colony formation in ATC cells. THZ531 causes a loss of elongating RNA polymerase II and suppresses gene expression in ATC cells. An integrative analysis of gene expression profiles and super-enhancer landscape, combining with functional assays, leads to the discovery of two new ATC cancer genes, ZC3H4 and NEMP1. Furthermore, CDK12 inhibition enhances the sensitivity of ATC cells to doxorubicin-mediated chemotherapy. Thus, these findings indicate that CDK12 is a potential therapeutic target for ATC treatment and its inhibition may help to overcome the chemoresistance in patients with ATC. (C) 2019 Elsevier Inc. All rights reserved.