HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis
Marta Palomo-Irigoyen, … , Marta Varela-Rey, Ashwin Woodhoo
Marta Palomo-Irigoyen, … , Marta Varela-Rey, Ashwin Woodhoo
Published April 21, 2020
Citation Information: J Clin Invest. 2020;130(7):3848-3864. https://doi.org/10.1172/JCI130379.
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HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Abstract

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.

Authors

Marta Palomo-Irigoyen, Encarni Pérez-Andrés, Marta Iruarrizaga-Lejarreta, Adrián Barreira-Manrique, Miguel Tamayo-Caro, Laura Vila-Vecilla, Leire Moreno-Cugnon, Nagore Beitia, Daniela Medrano, David Fernández-Ramos, Juan José Lozano, Satoshi Okawa, José L. Lavín, Natalia Martín-Martín, James D. Sutherland, Virginia Guitiérez de Juan, Monika Gonzalez-Lopez, Nuria Macías-Cámara, David Mosén-Ansorena, Liyam Laraba, C. Oliver Hanemann, Emanuela Ercolano, David B. Parkinson, Christopher W. Schultz, Marcos J. Araúzo-Bravo, Alex M. Ascensión, Daniela Gerovska, Haizea Iribar, Ander Izeta, Peter Pytel, Philipp Krastel, Alessandro Provenzani, Pierfausto Seneci, Ruben D. Carrasco, Antonio Del Sol, María Luz Martinez-Chantar, Rosa Barrio, Eduard Serra, Conxi Lazaro, Adrienne M. Flanagan, Myriam Gorospe, Nancy Ratner, Ana M. Aransay, Arkaitz Carracedo, Marta Varela-Rey, Ashwin Woodhoo

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Figure 6

RNA-Seq reveals that HuR controls key oncogenic pathways in MPNSTs.

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RNA-Seq reveals that HuR controls key oncogenic pathways in MPNSTs. (A) ...
(A) Heatmap representation of differentially expressed genes between shCtrl (n = 3) or shHuR#1-expressing (n = 3) ST88-14 MPNST cells (fold change >2; adjusted P value < 0.05). (B) Volcano plot of transcriptome profiles between shCtrl (n = 3) and shHuR#1-expressing (n = 3) ST88-14 MPNST cells. Red and blue dots represent genes significantly upregulated and downregulated, respectively, in shHuR#1-expressing cells (fold change >2; adjusted P value < 0.05). (C) GSEA analysis of shCtrl and shHuR#1-expressing ST88-14 MPNST cells for MSigDB oncogenic signatures. Gene sets with FDR Q values less than 0.25 are plotted relative to normalized enrichment score (NES). Categories with negative (left) and positive (right) NES are down- or upregulated, respectively, in shCtrl cells. Circles denote the number of enriched genes in each category, and colors represent FDR Q values as indicated.