REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling

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

Research output: Contribution to journalArticle

24 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)26137-26151
Number of pages15
JournalOncotarget
Volume7
Issue number18
DOIs
Publication statusPublished - May 1 2016

Keywords

  • Autophagy
  • Hypoxia
  • Neuroendocrine differentiation
  • Prostate cancer
  • REST

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Lin, T. P., Chang, Y. T., Lee, S. Y., Campbell, M., Wang, T. C., Shen, S. H., Chung, H. J., Chang, Y. H., Chiu, A. W., Pan, C. C., Lin, C. H., Chu, C. Y., Kung, H. J., Cheng, C. Y., & Chang, P. C. (2016). REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling. Oncotarget, 7(18), 26137-26151. https://doi.org/10.18632/oncotarget.8433