title: REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling.
abstract: Prostate cancer (PCa) with neuroendocrine differentiation (NED) is tightly associated with hormone refractory PCa (HRPC), an aggressive form of cancer that is nearly impossible to treat. Determining the mechanism of the development of NED may yield novel therapeutic strategies for HRPC. Here, we first demonstrate that repressor element-1 silencing transcription factor (REST), a transcriptional repressor of neuronal genes that has been implicated in androgen-deprivation and IL-6 induced NED, is essential for hypoxia-induced NED of PCa cells. Bioinformatics analysis of transcriptome profiles of REST knockdown during hypoxia treatment demonstrated that REST is a master regulator of hypoxia-induced genes. Gene set enrichment analysis (GSEA) of hypoxia and REST knockdown co-upregulated genes revealed their correlation with HRPC. Consistently, gene ontology (GO) analysis showed that REST reduction potential associated with hypoxia-induced tumorigenesis, NE development, and AMPK pathway activation. Emerging reports have revealed that AMPK activation is a potential mechanism for hypoxia-induced autophagy. In line with this, we demonstrate that REST knockdown alone is capable of activating AMPK and autophagy activation is essential for hypoxia-induced NED of PCa cells. Here, making using of in vitro cell-based assay for NED, we reveal a new role for the transcriptional repressor REST in hypoxia-induced NED and characterized a sequential molecular mechanism downstream of REST resulting in AMPK phosphorylation and autophagy activation, which may be a common signaling pathway leading to NED of PCa.
authors.affiliation: Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, R.O.C.|Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C.|Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Lin
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Yi-Ting
authors.initials: YT
authors.lastname: Chang
authors.affiliation: Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Sung-Yuan
authors.initials: SY
authors.lastname: Lee
authors.affiliation: UC Davis Cancer Center, University of California, Davis, CA, USA.
authors.forename: Mel
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.|Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Tien-Chiao
authors.initials: TC
authors.lastname: Wang
authors.affiliation: Department of Radiology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Shu-Huei
authors.initials: SH
authors.lastname: Shen
authors.affiliation: Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C.|Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Hsiao-Jen
authors.initials: HJ
authors.lastname: Chung
authors.affiliation: Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C.|Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C.
authors.forename: Yen-Hwa
authors.initials: YH
authors.lastname: Chang
authors.affiliation: Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, R.O.C.|Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Allen W
authors.initials: AW
authors.lastname: Chiu
authors.affiliation: Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Chin-Chen
authors.initials: CC
authors.lastname: Pan
authors.affiliation: Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, R.O.C.|Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Chi-Hung
authors.initials: CH
authors.lastname: Lin
authors.affiliation: Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan, R.O.C.
authors.forename: Cheng-Ying
authors.initials: CY
authors.lastname: Chu
authors.affiliation: UC Davis Cancer Center, University of California, Davis, CA, USA.|Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA.|Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan, R.O.C.|Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan, R.O.C.
authors.forename: Hsing-Jien
authors.initials: HJ
authors.lastname: Kung
authors.affiliation: Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan, R.O.C.|Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Chia-Yang
authors.initials: CY
authors.lastname: Cheng
authors.affiliation: Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.|Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C.
authors.forename: Pei-Ching
authors.initials: PC
authors.lastname: Chang
mesh_terms: D017209:Apoptosis; D001343:Autophagy; D014408:Biomarkers, Tumor / Q000378:metabolism; D002448:Cell Adhesion; D002454:Cell Differentiation; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000860:Hypoxia / Q000503:physiopathology*; D008297:Male; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D000099229:RE1-Silencing Transcription Factor
chemical_list: D014408:Biomarkers, Tumor; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
keywords: REST; autophagy; hypoxia; neuroendocrine differentiation; prostate cancer