REST 經由引發細胞自噬來調控缺氧所引起之攝護腺癌的神經內分泌分化
林子平1,2 張怡婷3 李松遠3 張佩靖3
台北榮民總醫院 泌尿部1; 陽明大學醫學院泌尿學科及書田泌尿學研究中心2; 陽明大學微生物及免疫學研究所3
Rest modulates hypoxia-induced neuroendocrine differentiation of prostate cancer cells by activating autophagy signaling
Tzu-Ping Lin1,2, Yi-Ting Chang3, Sung-Yuan Lee3, Pei-Ching Chang3
Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan1;
Department of Urology, School of Medicine, and Shu-Tien Urological Research Center, National Yang-Ming University, Taipei, Taiwan2;
Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan3
Purpose:
To study the role of element-1 silencing transcription factor(REST) in hypoxia induced neuroendocrine differentiation(NED) of prostate cancer.
Materials and Methods:
Prostate cancer cell line LNCaP was cultured in hypoxic chamber to induce NED. Neuroendocrine differentiation was quantified by neurite length measurement by phase-contrast optical microscope. Inducible REST knock down and overexpression LNCaP cell line was established and used to determine the effect of REST in NED in LNCaP cells. RNA was harvested from hypoxia-treated LNCaP, normoxia LNCaP, induced REST knock down LNCaP cells and sequenced with Illumina Genome AnalyzerII.
Results:
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 profile of REST knockdown with 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.
Conclusion:
REST knockdown alone is capable of activating AMPK and autophagy activation is essential for hypoxia-induced NED of PCa cells.