Yafei Yang1, Donggen Jiang1, Ziyu Zhou2,3, Haiyun Xiong1, Xiangwei Yang1, Guoyu Peng2,3, Wuchao Xia2,3, Shang Wang2,3, Hanqi Lei1, Jing Zhao4, Zhirong Qian4, Song Wu5,6, Jun Pang7. 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.
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.
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.
Authors: Yubao Wang; Tinghu Zhang; Nicholas Kwiatkowski; Brian J Abraham; Tong Ihn Lee; Shaozhen Xie; Haluk Yuzugullu; Thanh Von; Heyuan Li; Ziao Lin; Daniel G Stover; Elgene Lim; Zhigang C Wang; J Dirk Iglehart; Richard A Young; Nathanael S Gray; Jean J Zhao Journal: Cell Date: 2015-09-24 Impact factor: 41.582