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.
Highlights
Prostate cancer (PCa) is a leading cause of cancer morbidity and mortality in men
Since our recent report showed that repressor element-1 silencing transcription factor (REST) is essential for IL-6-induced NE differentiation (NED) [23], we sought to determine whether REST may function as a crucial factor for NED induced by hypoxia as well
The protein level of REST was analyzed by immunoblotting and a reduction of REST was identified at day 2 after hypoxia exposure (Figure 1C)
Summary
Prostate cancer (PCa) is a leading cause of cancer morbidity and mortality in men. Its incidence is exponentially correlated with aging. The mainstay of treatment for PCa is androgen deprivation therapy (ADT) via surgical or chemical castration strategies, which is not curative, as hormone-refractory (or castration-resistant) tumors eventually developed within few years after successful treatment by ADT [1]. Understanding of the mechanisms leading the development of HRPC will largely improve diagnostic, prognostic as well as therapeutic purposes. Identifying novel intervention strategies for the prevention or treatment of NE PCa is of great importance to improve the prognosis of HRPC. Though significant effort has been devoted to study the emergence of NE-like cells, the underlying mechanisms responsible for NED have yet to be fully identified. Multiple signaling pathways have been shown to induce NED in PCa cells, including androgen deprivation [5, 6] interleukin-6 (IL-6) treatment [7] and the recently identified contribution of hypoxia [8, 9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
