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Sci Rep. 2017 Mar 3;7:42795. doi: 10.1038/srep42795.

REST is a crucial regulator for acquiring EMT-like and stemness phenotypes in hormone-refractory prostate cancer.

Chang YT1, Lin TP2,3,4, Campbell M5, Pan CC6, Lee SH7, Lee HC7, Yang MH8,9,10,11,12,13, Kung HJ5,14,15,16, Chang PC1,12,13,17.

Author information

1
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan.
2
Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan.
3
Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan.
4
Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan.
5
UC Davis Comprehensive Cancer Center, University of California, Davis, CA 95616, USA.
6
Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.
7
Institute of Pharmacology, National Yang-Ming University, Taipei, Taiwan.
8
Institute of Clinical Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
9
Institute of Biotechnology in Medicine, National Yang-Ming University, Taipei 11221, Taiwan.
10
Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 11217, Taiwan.
11
Genomics Research Center, Academia Sinica, Taipei 11529, Taiwan.
12
Immunity and Inflammation Research Center, National Yang-Ming University, Taipei 11221, Taiwan.
13
Genome Research Center, National Yang-Ming University, Taipei, Taiwan.
14
Division of Molecular and Genomic Medicine, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 35053, Taiwan.
15
Department of Biochemistry and Molecular Medicine, University of California, Davis, CA 95616, USA.
16
Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, 250 Wu-Xin Street, Taipei City, Taiwan.
17
Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.

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.

PMID:
28256535
PMCID:
PMC5335619
DOI:
10.1038/srep42795
[Indexed for MEDLINE]
Free PMC Article

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