Jimenez Suarez, J.; Cimas, F. J.; Paricio, J. J.; Belandia, B.; Berrouayel Dahour, Y.; Arconada-Luque, E.; Matilla-Almazan, S.; Soffientini, C.; Percio, S.; Redondo-Garcia, S.; Garcia-Flores, N.; Garnes-Garcia, C.; Fernandez-Aroca, P.; Martinez-Gomez, J. J.; Fernandez-Aramburo, A.; Nam-Cha, S. H.; Rovida, E.; Pandiella, A.; Esparis-Ogando, A.; Pasquali, S.; Rodriguez-Manzaneque, J. C.; Del Peso, l.; Ruiz Hidalgo, M. j.; Sanchez-Prieto, R.

The ERK5 signaling pathway has recently emerged as a critical regulator of soft tissue sarcoma (STS) biology, contributing to tumor initiation, progression, and maintenance. In this study, we identify VCAN, a chondroitin sulfate proteoglycan, as a novel transcriptional target of ERK5 and a central mediator of ERK5-related oncogenesis. Through a combination of genetic (silencing, overexpression) and pharmacological approaches, applied in both a chemically induced murine sarcoma model and several human STS cell lines, we demonstrate that ERK5 positively regulates VCAN expression. Functionally, VCAN silencing (by shRNAs) recapitulates the phenotypes of ERK5 silencing, including impaired migration, adhesion, proliferation, and tumorigenesis. Conversely, VCAN overexpression rescues these effects, confirming its essential role in ERK5-mediated oncogenesis. Furthermore, transcriptomic profiling reveals that VCAN accounts for a substantial portion of ERK5-regulated gene expression program. Analyses of human STS patient samples reveal significantly elevated mRNA levels of both VCAN and ERK5 compared to normal tissues. Notably, a strong correlation between VCAN and ERK5 expression, both at mRNA and protein levels, emerged in biopsies from leiomyosarcomas and undifferentiated pleomorphic sarcomas. Together, these findings uncover VCAN as a key effector in ERK5-driven tumorigenesis and highlight the ERK5/VCAN signaling axis as a promising therapeutic target in soft tissue sarcomas.