title: REST is a crucial regulator for acquiring EMT-like and stemness phenotypes in hormone-refractory prostate cancer.
abstract: Castration-resistance prostate cancer (CRPC), also known as hormone-refractory prostate cancer (HRPC), requires immediate attention since it is not only resistant to androgen ablation, chemo- and radiotherapy, but also highly metastatic. Increasing evidence suggests that enrichment of neuroendocrine (NE) cells is associated with CRPC. Here, combined RNA-seq and ChIP-seq analysis reveals that REST is involved in epithelial-mesenchymal transition (EMT) and stemness acquisition in NE differentiated prostate cancer (PCa) cells via direct transcriptional repression of Twist1 and CD44. Specifically we show that short-term knockdown of REST induces NE differentiation of LNCaP cells. Long-term REST knockdown enhanced the expression of Twist1 and CD44, cell migration and sphere formation. Overexpression of REST in hormone-refractory CWR22Rv1 PCa cells significantly reduces Twist1 and CD44 expression, cell migration and sphere formation. Collectively, our study uncovers REST in regulating EMT and stemness properties of NE PCa cells and suggests that REST is a potential therapeutic target for CRPC.
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.|Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan.|Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Lin
authors.affiliation: UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
authors.forename: Mel
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chin-Chen
authors.initials: CC
authors.lastname: Pan
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Shu-Hui
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hsin-Chen
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.|Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei 11221, Taiwan.|Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.|Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.|Immunity and Inflammation Research Center, National Yang-Ming University, Taipei 11221, Taiwan.|Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Muh-Hwa
authors.initials: MH
authors.lastname: Yang
authors.affiliation: UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.|Division of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.|Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616, USA.|Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Xin Street, Taipei City, Taiwan.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.|Immunity and Inflammation Research Center, National Yang-Ming University, Taipei 11221, Taiwan.|Genome Research Center, National Yang-Ming University, Taipei, Taiwan.|Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.
authors.forename: Pei-Ching
authors.initials: PC
authors.lastname: Chang
mesh_terms: D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018960:Hyaluronan Receptors / Q000235:genetics*; D008297:Male; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D017423:Sequence Analysis, RNA; D051879:Twist-Related Protein 1 / Q000235:genetics*; D000099229:RE1-Silencing Transcription Factor
chemical_list: D018960:Hyaluronan Receptors; D009687:Nuclear Proteins; D012097:Repressor Proteins; D051879:Twist-Related Protein 1; D000099229:RE1-Silencing Transcription Factor; C497483:CD44 protein, human; C103173:TWIST1 protein, human