title: BRD4 Regulates EZH2 Transcription through Upregulation of C-MYC and Represents a Novel Therapeutic Target in Bladder Cancer.
abstract: People who develop bladder cancer frequently succumb to the intractable disease. Current treatment strategies are limited presumably due to the underlying molecular complexity and insufficient comprehension. Therefore, exploration of new therapeutic targets in bladder cancer remains necessary. Here, we identify that bromodomain-4 protein (BRD4), an important epigenome reader of bromodomain and extraterminal domain (BET) family member, is a key upstream regulator of enhancer of zeste homologue 2 (EZH2), and represents a novel therapeutic target in bladder cancer. We found that BRD4 was significantly overexpressed in bladder cancer cells and tissues. Inhibition of BRD4 decreased bladder cancer cell proliferation concomitantly with the accumulation of cell apoptosis in vitro and suppressed tumor growth in vivo We further found that suppression of BRD4 decreased the mRNA and protein levels of EZH2, which was reversed by ectopic expression of C-MYC In particular, individual silencing of BRD4 using shRNA or the BET inhibitor JQ1 strikingly diminished the recruitment of C-MYC to EZH2 promoter in bladder cancer. Briefly, our research reveals that BRD4 positively regulates EZH2 transcription through upregulation of C-MYC, and is a novel promising target for pharmacologic treatment in transcriptional program intervention against this intractable disease. Mol Cancer Ther; 15(5); 1029-42. ©2016 AACR.
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
authors.forename: Xinchao
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Oncology, The Fifth Hospital of Wuhan, Hubei Province, Wuhan, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Tao
authors.affiliation: Department of Urology, The First Hospital of Wuhan, Hubei Province, Wuhan, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Xiang
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
authors.forename: Xingyuan
authors.initials: X
authors.lastname: Xiao
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
authors.forename: Miao
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Luo
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China. jiangguosongdoc@hotmail.com zfq2016@163.com.
authors.forename: Fuqing
authors.initials: F
authors.lastname: Zeng
authors.affiliation: Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Hubei Province, Wuhan, China. jiangguosongdoc@hotmail.com zfq2016@163.com.
authors.forename: Guosong
authors.initials: G
authors.lastname: Jiang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism*; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics*; D014157:Transcription Factors / Q000378:metabolism*; D015533:Transcriptional Activation; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D000092468:Bromodomain Containing Proteins
chemical_list: D018797:Cell Cycle Proteins; D000071221:Enhancer of Zeste Homolog 2 Protein; D009687:Nuclear Proteins; D016271:Proto-Oncogene Proteins c-myc; D014157:Transcription Factors; C441289:BRD4 protein, human; D000092468:Bromodomain Containing Proteins; C498409:EZH2 protein, human