Prostate cancers often exhibit alterations in genes that are involved in differentiation, and they also co-express some basal and luminal markers, pointing to defects in differentiation contributing to tumorigenesis. In their study on page 1952, Cindy Miranti and colleagues sought to understand how the p38-MAPK, MYC and Notch signalling pathways, known to be involved in differentiation, work together in normal prostate differentiation. By utilising an in vitro differentiation model of human basal prostate epithelial cells, they first asked whether the p38-MAPK family is involved in the regulation of Notch3, whose induction coincides with the appearance of suprabasal cells during prostate differentiation. Indeed, inhibition or knockdown of p38-MAPK prevented differentiation, whereas constitutive activation of p38-MAPK increased the levels of Notch3 in a MYC-dependent manner. This suggests that Notch3 is a MYC target that is downstream of p38-MAPK, whereas it had been thought to act upstream of MYC. With regard to the underlying mechanisms, the authors show that Notch3 is regulated both transcriptionally, including via MYC, and post-transcriptionally, through a p38-MAPK-mediated increase in its mRNA stability. Taken together, this work thus provides new insights into the crosstalk between p38-MAPK, MYC and Notch signalling during differentiation that could be exploited for targeting tumours that arise from dysregulated differentiation programmes.
