Gene expression patterns in human prostate stem cell differentiation

The identification of phenotypic differences between stem cells (SCs) and their more differentiated counterparts is crucial for designing novel SC-based therapeutics for prostate cancer (CaP). RARRES1 and LXN were identified as two homologous genes whose expression was highly significantly down-regulated in the SC fraction compared to more differentiated epithelial cells. The overall aim of this study was to investigate the expression, regulation and function of the SC-silenced genes RARRES1 and LXN, and their potential interacting partner CPA4 in prostate epithelial differentiation and CaP.

We showed that RARRES1 and LXN were SC-silenced genes, whose expression was induced by the pro-differentiation agent all-trans retinoic acid (atRA). AtRA induced expression to a higher extent in the most differentiated cells than the SC fraction, suggesting that this sub-population was less responsive to atRA. Importantly, siRNA suppression of RARRES1 and LXN enhanced the SC properties of primary prostate cultures, as shown by a significant increase in their colony forming ability. Expression of both RARRES1 and LXN was co-ordinately repressed by DNA methylation in CaP cell lines and inhibition of RARRES1 and LXN increased the invasive capacity of primary prostate cultures, which also fully rescued an inhibitory effect induced by atRA. Despite their homology and adjacent location on chromosome 3, we provide evidence that RARRES1 and LXN reside within different sub-cellular compartments; RARRES1 is not a plasma membrane protein as previously supposed but is located in the endoplasmic reticulum, while LXN is localised to the nucleus of prostate epithelial cells.

These data provide novel results identifying two potential tumour suppressor genes as co-ordinately regulated, SC-silenced genes that function to suppress the invasion and colony forming ability of CaP cells. Work now should be focussed on determining whether re-administration of RARRES1 and LXN would be a valid differentiation strategy for the treatment, and potentially eradication, of CaP.