VCAN Is Essential for ERK5-Driven Tumorigenesis in Soft Tissue Sarcoma

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.

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Publication Details

Journal
International Journal of Biological Sciences
Published
2026-02-04
DOI
https://doi.org/10.7150/ijbs.121402
Primary Topic
Melanoma and MAPK Pathways
Type
article
Field-Weighted Citation Impact
0.00

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article

VCAN Is Essential for ERK5-Driven Tumorigenesis in Soft Tissue Sarcoma

José Joaquín Paricio, Francisco J. Cimas, Natalia García-Flores, Cesare Soffientini et al.
International Journal of Biological Sciences
Melanoma and MAPK Pathways
article

VCAN Is Essential for ERK5-Driven Tumorigenesis in Soft Tissue Sarcoma

José Joaquín Paricio, Francisco J. Cimas, Natalia García-Flores, Cesare Soffientini, Borja Belandia, JUAN CARLOS RODRIGUEZ-MANZANEQUE, María José Ruiz‐Hidalgo, Stefano Percio, Silvia Redondo-García, Elisabetta Rovida, Yosra Berrouayel, Juan Jesús Martínez-Gómez, Sandro Pasquali, Atanasio Pandiella, Pablo Fernández-Aroca, Azucena Esparís-Ogando, Syong Hyun Nam-Cha, Sofía Matilla-Almazán, Luis Del Peso, Elena Arconada-Luque, Jaime Jiménez-Suárez, Cristina Garnés-García, Antonio Fernández-Aramburo
article en

Abstract

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.

International Journal of Biological SciencesVol. 22(5)
Consejo Superior de Investigaciones Científicas (ES), Instituto de Investigaciones Biomédicas Sols-Morreale (ES), Centro de Investigación Biomédica en Red de Enfermedades Respiratorias (ES), Centro de Investigación Biomédica en Red (ES), Instituto Ramón y Cajal de Investigación Sanitaria (ES), Centro de Investigación del Cáncer (ES), Pfizer-University of Granada-Junta de Andalucía Centre for Genomics and Oncological Research (ES), Complejo Hospitalario Universitario de Albacete (ES), Fondazione IRCCS Istituto Nazionale dei Tumori (IT), University of Florence (IT), Universidad Autónoma de Madrid (ES), University of Castilla-La Mancha (ES)
Ministero della Salute, Ministerio de Economía y Competitividad, Associazione Italiana per la Ricerca sul Cancro, Universidad de Castilla-La Mancha, Junta de Comunidades de Castilla-La Mancha, Centro de Investigación Biomédica en Red de Cáncer, Instituto de Salud Carlos III, Agencia Estatal de Investigación, European Social Fund
Openalex Percentile: Top 56%
Melanoma and MAPK Pathways
DOIOpen Access PDFOpenAlex
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