Down-regulation of RE-1 silencing transcription factor (REST) in advanced prostate cancer by hypoxia-induced miR-106b~25

Abstract

Clinically aggressive prostate cancer (PCa) is linked to androgen resistance, metastasis, and expression of neuroendocrine markers. To understand mechanism(s) of neuroendocrine differentiation (NED) of PCa epithelia, we compared neuronal differentiation occurring during embryogenesis, in primary cultures of neural crest (NC) cells, and NED in PCa cell lines (LNCaP and PC3). We demonstrate, hypoxia promotes neuronal and neuroendocrine differentiation of NC cells and PCa cells, respectively, by inducing the miR-106b~25 cluster. In turn, miR-106b~25 comprised of miR-106b, miR-93 and miR-25, down-regulates the transcriptional repressor REST, which represses neuron-specific protein-coding and miRNA genes. In prostate tumors of high Gleason score (≥ 8), an inverse trend was observed between REST and miR-106b~25 induction. Employing miRNA PCR arrays, we identified miRNAs up-regulated by hypoxia in LNCaP cells and REST-knockdown in NC cells. Significantly, a subset of miRNAs (miR-9, miR-25, miR-30d and miR302b) is up-regulated in high Gleason score (≥ 8) PCa, suggesting a mechanism by which NED contributes to PCa malignancy. We propose that loss of REST and induction of this set of microRNAs can serve as potential novel clinical markers of advanced PCa.

miR-25 Modulates Invasiveness and Dissemination of Human Prostate Cancer Cells via Regulation of αv- and α6-Integrin Expression

“…Consistent with our findings, the expression of the miR-106b-25 cluster appears to mediate neuronal differentiation of adult neural stem/progenitor cells and, interestingly, induction of miR-106b-25 in hypoxic conditions was recently linked to increased expression of neuronal markers in prostate cancer cell lines (43,44). Thus, our work and these results suggest that lower miR-25 expression is needed to maintain stem/progenitor phenotype and its increase is associated with cellular differentiation.…”

Selective repression of gene expression in neuropathic pain by the neuron-restrictive silencing factor/repressor element-1 silencing transcription (NRSF/REST)

“…Finally, our knowledge of how NRSF levels are regulated by miRNA following neural injury is limited. Several miRNAs have been reported to target NRSF, both directly and indirectly, and for several of these miRNAs, NRSF mediates reciprocal repression [28, 42, 62, 65]. …”

REST is a crucial regulator for acquiring EMT-like and stemness phenotypes in hormone-refractory prostate cancer

“…NE-like cell development relies on a network of transcriptional reprogramming that controls the acquisition and maintenance of neuronal features. Recent reports including ours provide evidence showing that repressor element-1 (RE-1) silencing transcription factor (REST) expression is significantly reduced in relapsed PCa tissue912 and reduction of REST is responsible for NED of PCa cells910111213. REST was originally identified as a transcription repressor for neuron-specific genes in neuronal progenitor and non-neuronal cells14.…”

“…One recent report provided an explanation for this contradiction by suggesting a passage-dependent response, as REST deficiency impaired pluripotency of ESCs in early passage and restoration of impaired self-renewal upon prolonged culture30. In PCa, REST was found to be a mediator of AR9 and induced NED upon downregulation101112. However, whether a prolonged decrease of REST results in NE-like cells acquiring stemness is largely unknown.…”