Research Papers:
REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling
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Abstract
Tzu-Ping Lin1,2,3, Yi-Ting Chang12, Sung-Yuan Lee12, Mel Campbell4, Tien-Chiao Wang3,12, Shu-Huei Shen5, Hsiao-Jen Chung2,3, Yen-Hwa Chang2,3, Allen W. Chiu1,2, Chin-Chen Pan6, Chi-Hung Lin1,12, Cheng-Ying Chu8, Hsing-Jien Kung4,7,8,9, Chia-Yang Cheng10,12, Pei-Ching Chang11,12
1Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, R.O.C
2Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C
3Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C
4UC Davis Cancer Center, University of California, Davis, CA, USA
5Department of Radiology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan, R.O.C
6Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan, R.O.C
7Department of Biochemistry and Molecular Medicine, University of California, Davis, CA, USA
8Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan, R.O.C
9Division of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Miaoli County, Taiwan, R.O.C
10Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan, R.O.C
11Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C
12Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C
Correspondence to:
Pei-Ching Chang, email: [email protected]
Chia-Yang Cheng, email: [email protected]
Keywords: REST, hypoxia, neuroendocrine differentiation, prostate cancer, autophagy
Received: September 27, 2015 Accepted: March 10, 2016 Published: March 28, 2016
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.
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