PRAMEF2-mediated dynamic regulation of YAP signaling promotes tumorigenesis

Menée in vitro et à l'aide d'un modèle murin, cette étude met en évidence un mécanisme par lequel la protéine PRAMEF2 favorise la tumorigenèse en induisant l'accumulation de la protéine YAP dans le noyau cellulaire via la dégradation protéasomale de la kinase LATS1

Résumé en anglais

PRAMEF2 belongs to the PRAME multigene family of cancer testis antigens, which serve as biomarkers for several cancers. However, its role in tumorigenesis remains unexplored. Here, we delineate PRAMEF2 regulation under low-nutrient conditions. We also show that it promotes proteasomal degradation of LATS1 kinase of the Hippo/YAP pathway. LATS1 down-regulation triggers nuclear accumulation of the transcriptional coactivator YAP, which induces the expression of proliferative and metastatic genes. Thus, PRAMEF2 promotes malignant phenotype in a YAP-dependent manner. Taken together, our findings reveal a pivotal role for PRAMEF2 in determining YAP oncogenic signaling, which has key implications for tumorigenesis.PRAMEF2 is a member of the PRAME multigene family of cancer testis antigens, which serve as prognostic markers for several cancers. However, molecular mechanisms underlying its role in tumorigenesis remain poorly understood. Here, we report that PRAMEF2 is repressed under conditions of altered metabolic homeostasis in a FOXP3-dependent manner. We further demonstrate that PRAMEF2 is a BC-box containing substrate recognition subunit of Cullin 2–based E3 ubiquitin ligase complex. PRAMEF2 mediates polyubiquitylation of LATS1 kinase of the Hippo/YAP pathway, leading to its proteasomal degradation. The site for ubiquitylation was mapped to the conserved Lys860 residue in LATS1. Furthermore, LATS1 degradation promotes enhanced nuclear accumulation of the transcriptional coactivator YAP, resulting in increased expression of proliferative and metastatic genes. Thus, PRAMEF2 promotes malignant phenotype in a YAP-dependent manner. Additionally, elevated PRAMEF2 levels correlate with increased nuclear accumulation of YAP in advanced grades of breast carcinoma. These findings highlight the pivotal role of PRAMEF2 in tumorigenesis and provide mechanistic insight into YAP regulation.All study data are included in the article and/or SI Appendix.