Reduced expression of the neuron restrictive silencer factor permits transcription of glycine receptor α1 subunit in small-cell lung cancer cells

Regulation of the NRSF/REST gene by methylation and CREB affects the cellular phenotype of small-cell lung cancer

“…Here, we show that cell differentiation and growth in SCLC mediated by NRSF/REST are subject to upstream regulation by methylation, which modulates downstream AKT2 signalling. The expression of neuronal genes is a phenotypic hallmark of SCLC tissue and cell lines (Coulson et al, 2000;Gurrola-Diaz et al, 2003;Neumann et al, 2004;Onganer et al, 2005;Moss et al, 2009). In this study, we determined transcripts of various neuronal marker genes in SCLC lines and correlated expression levels with those of NRSF/REST and its splice variant sNRSF, thus extending other reports on SCLC lines with reduced NRSF/REST expression.…”

“…It has become apparent that NRSF/REST acts as an important determinant of cell differentiation in SCLC (Coulson et al, 2000;Gurrola-Diaz et al, 2003;Neumann et al, 2004;Onganer et al, 2005). Here, we show that cell differentiation and growth in SCLC mediated by NRSF/REST are subject to upstream regulation by methylation, which modulates downstream AKT2 signalling.…”

“…Starting from the observation that low expression levels of NRSF/REST in the SCLC lines H69, H146 and H209 correlated with the expression of neuronal markers like L1-CAM, NCAM and voltage-gated calcium channels (Neumann et al, 2004), and glycine receptor alpha 1 subunit (Gurrola-Diaz et al, 2003), we identified additional SCLC lines that lacked expression of NRSF/REST and showed transcription of de-regulated neuronal transcripts. Ten SCLC and one NSCLC lines, a lung fibroblast cell line and normal lung tissue, were analysed for transcription patterns of NRSF/REST and putative regulated genes (Figure 1).…”

“…These splice variants possess an additional conserved exon between exons 3 and 4, leading to a premature stop codon. The expression of the human Rest4 analogue sNRSF was found to be abundant in SCLC cell lines (Coulson et al, 2000;Gurrola-Diaz et al, 2003).…”

“…NRSF/REST is known to be degraded by SCFbeta-TRP, in which failure to degrade NRSF/REST attenuated neuronal cell differentiation (Westbrook et al, 2008). NRSF/REST was identified as a putative tumour suppressor in different colon and SCLC cell lines where reduced or complete loss of NRSF/REST gene expression occurred (Gurrola-Diaz et al, 2003;Neumann et al, 2004;Westbrook et al, 2005). In colon cancer, loss of NRSF/REST expression was due to a frameshift mutation, which resulted in protein truncation (Westbrook et al, 2005).…”