Reprimo (RPRM): A Tumor Suppressor That Induces Extrinsic Apoptosis via YAP Signaling.

Reprimo (encoded by RPRM) was initially identified as a p53 target gene in 2000 and functions as a tumor suppressor. Promoter hypermethylation of RPRM is frequently observed in various cancers, suggesting that it is transcriptionally silenced during tumorigenesis. Previous studies have reported that overexpression of RPRM induces G2/M cell cycle arrest, inhibits cell proliferation, promotes apoptosis, and increases cellular sensitivity to DNA damage. However, the molecular function of Reprimo is not completely understood. In particular, our recent studies revealed that Reprimo has a novel extracellular function, being secreted outside the cells where it functions to induce apoptosis in its target cells. Furthermore, we found that this apoptosis pathway is novel, mediated by a signaling pathway composed of p53-Reprimo-protocadherin family-Hippo-YAP/TAZ-p73. Reprimo is the first example of an extracellular ligand that induces cell death by modulating YAP activity and is a unique upstream regulator of Hippo signaling. This review summarizes current knowledge of the tumor-suppressive mechanisms of Reprimo, with an emphasis on its unique extracellular function and discusses potential future research directions and clinical applications in cancer therapy.