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.
Oncotarget. 2016 Mar 28 [Epub ahead of print]
Tzu-Ping Lin, Yi-Ting Chang, Sung-Yuan Lee, Mel Campbell, Tien-Chiao Wang, Shu-Huei Shen, Hsiao-Jen Chung, Yen-Hwa Chang, Allen W Chiu, Chin-Chen Pan, Chi-Hung Lin, Cheng-Ying Chu, Hsing-Jien Kung, Chia-Yang Cheng, Pei-Ching Chang
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., Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan, R.O.C., UC Davis Cancer Center, University of California, Davis, CA, USA., Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, R.O.C., Department of Radiology, Taipei Veterans General Hospital, 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, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan, R.O.C., Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, R.O.C., Department of Pathology, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan, R.O.C., Institute of Clinical Medicine, National Yang Ming University, Taipei, Taiwan, R.O.C., Institute for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei City, Taiwan, R.O.C., UC Davis Cancer Center, University of California, Davis, CA, USA., Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan, R.O.C., Center for Infectious Disease and Cancer Research, Kaohsiung Medical University, Kaohsiung, Taiwan, R.O.C.