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

研究成果: 雜誌貢獻文章

21 引文 (Scopus)

摘要

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.
原文英語
頁(從 - 到)26137-26151
頁數15
期刊Oncotarget
7
發行號18
DOIs
出版狀態已發佈 - 五月 1 2016

指紋

Transcriptional Silencer Elements
Autophagy
Prostatic Neoplasms
Transcription Factors
AMP-Activated Protein Kinases
Hormones
Genes
Gene Ontology
Hypoxia
Computational Biology
Transcriptome
Androgens
Interleukin-6
Carcinogenesis
Phosphorylation

ASJC Scopus subject areas

  • Oncology

引用此文

Lin, T. P., Chang, Y. T., Lee, S. Y., Campbell, M., Wang, T. C., Shen, S. H., ... 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

REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling. / Lin, Tzu Ping; Chang, Yi Ting; Lee, Sung Yuan; Campbell, Mel; Wang, Tien Chiao; Shen, Shu Huei; Chung, Hsiao Jen; Chang, Yen Hwa; Chiu, Allen W.; Pan, Chin Chen; Lin, Chi Hung; Chu, Cheng Ying; Kung, Hsing Jien; Cheng, Chia Yang; Chang, Pei Ching.

於: Oncotarget, 卷 7, 編號 18, 01.05.2016, p. 26137-26151.

研究成果: 雜誌貢獻文章

Lin, TP, Chang, YT, Lee, SY, Campbell, M, Wang, TC, Shen, SH, Chung, HJ, Chang, YH, Chiu, AW, Pan, CC, Lin, CH, Chu, CY, Kung, HJ, Cheng, CY & Chang, PC 2016, 'REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling', Oncotarget, 卷 7, 編號 18, 頁 26137-26151. https://doi.org/10.18632/oncotarget.8433
Lin, Tzu Ping ; Chang, Yi Ting ; Lee, Sung Yuan ; Campbell, Mel ; Wang, Tien Chiao ; Shen, Shu Huei ; Chung, Hsiao Jen ; Chang, Yen Hwa ; Chiu, Allen W. ; Pan, Chin Chen ; Lin, Chi Hung ; Chu, Cheng Ying ; Kung, Hsing Jien ; Cheng, Chia Yang ; Chang, Pei Ching. / REST reduction is essential for hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling. 於: Oncotarget. 2016 ; 卷 7, 編號 18. 頁 26137-26151.
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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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AU - Campbell, Mel

AU - Wang, Tien Chiao

AU - Shen, Shu Huei

AU - Chung, Hsiao Jen

AU - Chang, Yen Hwa

AU - Chiu, Allen W.

AU - Pan, Chin Chen

AU - Lin, Chi Hung

AU - Chu, Cheng Ying

AU - Kung, Hsing Jien

AU - Cheng, Chia Yang

AU - Chang, Pei Ching

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N2 - 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.

AB - 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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