Targeting Super-Enhancer-Driven Oncogenic Transcription by CDK7 Inhibition in Anaplastic Thyroid Carcinoma
Targeting Super-Enhancer-Driven Oncogenic Transcription by CDK7 Inhibition in Anaplastic Thyroid Carcinoma
复制标题
通过抑制 CDK7 靶向未变性甲状腺癌中超级增强子驱动的致癌转录
DOI：
10.1089/thy.2018.0550
复制
发表时间：
2019-05-03
期刊：
影响因子：
6.6
通讯作者：
Chen, Yupeng
中科院分区：
文献类型：
--
作者：
Cao, Xinyi;Dang, Lin;Chen, Yupeng
背景：未分化甲状腺癌（ATC）是最具侵袭性的恶性肿瘤之一，目前尚无有效的治疗方法。ATC致癌的分子机制仍知之甚少。本研究的目的是探讨超级增强子（SE）驱动的致癌转录成瘾在ATC进展中的机制和功能，并确定ATC治疗的新药物靶点。
方法：进行高通量化学筛选以确定抑制ATC细胞生长的新药。采用细胞活力测定、集落形成分析、细胞周期分析和动物研究来检测药物治疗对ATC进展的影响。进行染色质免疫沉淀测序以建立ATC的SE图谱。通过对RNA测序、染色质免疫沉淀测序和CRISPR/Cas9介导的基因编辑进行综合分析来确定THZ1的靶基因。进行药物组合分析以评估药物协同作用。分析患者样本以评估ATC中预后的候选生物标志物。
结果：通过高通量化学筛选，THZ1（一种细胞周期蛋白依赖性激酶7（CDK7）的共价抑制剂）被确定为一种有效的抗ATC化合物。ATC细胞（而非甲状腺乳头状癌细胞）对CDK7抑制异常敏感。对基因表达谱和SE特征的综合分析表明，SE介导的致癌转录扩增介导了ATC细胞对THZ1治疗的易感性。将这种综合分析与功能测定相结合，发现了一些ATC的新型癌基因，包括PPP1R15A、SMG9和KLF2。用胍那苄或Sephin1抑制PPP1R15A可极大地抑制ATC生长。值得注意的是，在ATC组织样本中，PPP1R15A的表达水平与CDK7的表达相关。PPP1R15A和CDK7的高表达均与ATC患者不良的临床预后相关。重要的是，抑制CDK7或PPP1R15A可使ATC细胞对常规化疗敏感。
结论：综上所述，这些发现证明了ATC病理生物学中的转录成瘾，并确定CDK7和PPP1R15A为ATC潜在的生物标志物和治疗靶点。
Background: Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies, with no effective treatment currently available. The molecular mechanisms of ATC carcinogenesis remain poorly understood. The objective of this study was to investigate the mechanisms and functions of super-enhancer (SE)-driven oncogenic transcriptional addiction in the progression of ATC and identify new drug targets for ATC treatments. Methods: High-throughput chemical screening was performed to identify new drugs inhibiting ATC cell growth. Cell viability assay, colony formation analysis, cell-cycle analysis, and animal study were used to examine the effects of drug treatments on ATC progression. Chromatin immunoprecipitation sequencing was conducted to establish a SE landscape of ATC. Integrative analysis of RNA sequencing, chromatin immunoprecipitation sequencing, and CRISPR/Cas9-mediated gene editing was used to identify THZ1 target genes. Drug combination analysis was performed to assess drug synergy. Patient samples were analyzed to evaluate candidate biomarkers of prognosis in ATC. Results: THZ1, a covalent inhibitor of cyclin-dependent kinase 7 (CDK7), was identified as a potent anti-ATC compound by high-throughput chemical screening. ATC cells, but not papillary thyroid carcinoma cells, are exceptionally sensitive to CDK7 inhibition. An integrative analysis of both gene expression profiles and SE features revealed that the SE-mediated oncogenic transcriptional amplification mediates the vulnerability of ATC cells to THZ1 treatment. Combining this integrative analysis with functional assays led to the discovery of a number of novel cancer genes of ATC, including PPP1R15A, SMG9, and KLF2. Inhibition of PPP1R15A with Guanabenz or Sephin1 greatly suppresses ATC growth. Significantly, the expression level of PPP1R15A is correlated with CDK7 expression in ATC tissue samples. Elevated expression of PPP1R15A and CDK7 are both associated with poor clinical prognosis in ATC patients. Importantly, CDK7 or PPP1R15A inhibition sensitizes ATC cells to conventional chemotherapy. Conclusions: Taken together, these findings demonstrate transcriptional addiction in ATC pathobiology and identify CDK7 and PPP1R15A as potential biomarkers and therapeutic targets for ATC.