Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China.
Cell Oncol (Dordr). 2021 Aug;44(4):871-887. doi: 10.1007/s13402-021-00608-x. Epub 2021 Apr 27.
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.
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.
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.
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.
转录成瘾在维持癌细胞的标志性特征方面起着关键作用。因此，针对超级增强子（SEs），调节致癌基因的转录活性，已成为癌症治疗的一种有吸引力的策略。然而，目前膀胱癌（BC）中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 中 SE 景观的详细信息，并研究 BC 治疗的新潜在药物靶点。
我们采用 THZ1 作为一种有效的、特异性的 CDK7 抑制剂。进行了体外和体内研究，以研究 THZ1 对 BC 细胞的抗癌和诱导凋亡作用。进行了全转录组测序（RNA-seq）和染色质免疫沉淀测序（ChIP-seq），以研究 BC 细胞中 SE 相关致癌转录的机制和功能。
我们发现 THZ1 是一种有效的、有抑制活性的 BC 细胞抑制剂。对 THZ1 敏感和 SE 相关的致癌基因进行综合分析，得到了一些潜在的新药物靶点，包括 DDIT4、B4GALT5、PSRC1 和 MED22。THZ1 和 DDIT4 抑制剂雷帕霉素联合治疗可有效抑制 BC 细胞生长。此外，我们发现 THZ1 和雷帕霉素可使 BC 细胞对常规化疗敏感。
我们的数据表明，通过整合 RNA-seq 和 ChIP-seq 数据探索与 SE 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。
