Purpose

Transcriptional addiction plays a pivotal role in maintaining the hallmarks of cancer cells. Thus, targeting super-enhancers (SEs), which modulate the transcriptional activity of oncogenes, has become an attractive strategy for cancer therapy. As yet, however, the molecular mechanisms of this process in bladder cancer (BC) remain to be elucidated. Here, we aimed to provide detailed information regarding the SE landscape in BC and to investigate new potential pharmaceutical targets for BC therapy.

Methods

We employed THZ1 as a potent and specific CDK7 inhibitor. In vitro and in vivo studies were carried out to investigate the anticancer and apoptosis-inducing effects of THZ1 on BC cells. Whole-transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation sequencing (ChIP-seq) were performed to investigate the mechanism and function of SE-linked oncogenic transcription in BC cells.

Results

We found that THZ1 serves as an effective and potent inhibitor with suppressive activity against BC cells. An integrative analysis of THZ1-sensitive and SE-associated oncogenes yielded potential new pharmaceutical targets, including DDIT4, B4GALT5, PSRC1 and MED22. Combination treatment with THZ1 and the DDIT4 inhibitor rapamycin effectively suppressed BC cell growth. In addition, we found that THZ1 and rapamycin sensitized BC cells to conventional chemotherapy.

Conclusions

Our data indicate that exploring BC gene regulatory mechanisms associated with SEs through integrating RNA-seq and ChIP-seq data improves our understanding of BC biology and provides a basis for innovative therapies.

中文翻译：

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CDK7阻断抑制膀胱癌中与超增强子相关的癌基因

目的

转录成瘾在维持癌细胞的特征方面起着关键作用。因此，靶向调节癌基因转录活性的超级增强子（SEs）已成为癌症治疗的一种有吸引力的策略。然而，到目前为止，膀胱癌 (BC) 这一过程的分子机制仍有待阐明。在这里，我们旨在提供有关 BC SE 领域的详细信息，并研究 BC 治疗的新潜在药物靶点。

方法

我们使用 THZ1 作为一种有效且特异性的 CDK7 抑制剂。进行了体外和体内研究以研究 THZ1 对 BC 细胞的抗癌和诱导细胞凋亡的作用。进行全转录组测序 (RNA-seq) 和染色质免疫沉淀测序 (ChIP-seq) 以研究 BC 细胞中 SE 连锁致癌转录的机制和功能。

结果

我们发现 THZ1 是一种有效且有效的抑制剂，对 BC 细胞具有抑制活性。对 THZ1 敏感和 SE 相关癌基因的综合分析产生了潜在的新药物靶点，包括 DDIT4、B4GALT5、PSRC1 和 MED22。THZ1 和 DDIT4 抑制剂雷帕霉素的联合治疗有效地抑制了 BC 细胞的生长。此外，我们发现 THZ1 和雷帕霉素使 BC 细胞对常规化疗敏感。

结论

我们的数据表明，通过整合 RNA-seq 和 ChIP-seq 数据探索与 SEs 相关的 BC 基因调控机制可以提高我们对 BC 生物学的理解，并为创新疗法提供基础。