Ninety-five percent of melanomas, as well as many breast and neuroblastoma tumours, overexpress a tumour antigen called preferentially expressed antigen in melanoma (PRAME), but little is known about its potential oncogenic function. In their Cell paper, René Bernards and colleagues show that PRAME is an important modulator of retinoic acid signalling that promotes cell proliferation and survival.

To investigate the function of PRAME, the authors analysed its protein sequence to identify conserved motifs. They found that in addition to a nuclear localization signal, PRAME contained seven putative binding domains for nuclear receptors such as the retinoic acid receptor (RAR). Luciferase reporter assays showed that PRAME was indeed able to repress transcription of genes that contain retinoic acid-responsive elements, but not genes that are activated by other nuclear receptors such as the oestrogen receptor or peroxisome proliferator-activated receptor.

Retinoic acid is a signalling molecule that regulates gene expression through its interaction with the retinoic acid receptors RARα, RARβ or RARγ. These RARs can heterodimerize with the retinoid X receptor (RXR) and bind to retinoic acid-responsive elements to activate gene transcription. In the absence of retinoic acid, RARs remain bound to DNA and repress gene expression. Bernards and colleagues demonstrated that PRAME represses RAR-mediated gene transcription in a ligand (retinoic acid)-dependent manner. They showed that PRAME interacts with RAR directly, and expression of PRAME in F9 mouse embryonic carcinoma cells prevented retinoic acid-induced differentiation, cell-cycle arrest and apoptosis. Conversely, PRAME knockdown in melanoma restored retinoic acid signalling, as well as significantly inhibiting melanoma growth in the presence of retinoic acid in a melanoma xenograft model.

So, how does PRAME repress RAR-mediated gene transcription? Transcriptional repression often involves the recruitment of histone deacetylases (HDACs), but treatment of PRAME-expressing cells with the HDAC inhibitor trichostatin A did not affect transcriptional repression by PRAME. However, preliminary evidence has indicated that in some human tumours the expression of PRAME correlates with the expression of EZH2, a member of the polycomb group of proteins that are involved in gene silencing. Tagged versions of EZH2 and PRAME were used to confirm that these two proteins interact and repress retinoic acid-dependent RAR-mediated gene transcription. Furthermore, short hairpin RNAs that knock down the expression of either EZH2 or PRAME restored retinoic acid-mediated arrest and apoptosis in melanoma cell lines.

The authors conclude that PRAME is involved in tumour progression rather than tumour initiation by suppressing retinoic acid signalling. However, whether PRAME is a potential therapeutic target for treating melanoma and other cancers requires further investigation.