1. Academic Validation
  2. CDK7 blockade suppresses super-enhancer-associated oncogenes in bladder cancer

CDK7 blockade suppresses super-enhancer-associated oncogenes in bladder cancer

  • Cell Oncol (Dordr). 2021 Aug;44(4):871-887. doi: 10.1007/s13402-021-00608-x.
Yafei Yang  # 1 Donggen Jiang  # 1 Ziyu Zhou  # 2 3 Haiyun Xiong 1 Xiangwei Yang 1 Guoyu Peng 2 3 Wuchao Xia 2 3 Shang Wang 2 3 Hanqi Lei 1 Jing Zhao 4 Zhirong Qian 4 Song Wu 5 6 Jun Pang 7
Affiliations

Affiliations

  • 1 Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China.
  • 2 Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China.
  • 3 Shenzhen Following Precision Medical Research Institute, Luohu Hospital Group, Shenzhen, 518000, China.
  • 4 Research Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, 518107, China.
  • 5 Urology Institute of Shenzhen University, The Third Affiliated Hospital of Shenzhen University, Shenzhen University, Shenzhen, 518000, China. wusong@szu.edu.cn.
  • 6 Shenzhen Following Precision Medical Research Institute, Luohu Hospital Group, Shenzhen, 518000, China. wusong@szu.edu.cn.
  • 7 Department of Urology, Kidney and Urology Center, Pelvic Floor Disorders Center, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, China. pangjun2@mail.sysu.edu.cn.
  • # Contributed equally.
Abstract

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.

Keywords

Bladder cancer; CDK7; Super enhancer; THZ1; Transcriptional addiction.

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