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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Research Article Cell biology Oncology

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 9

HuR activates key oncogenic programs by regulating the Wnt/β-catenin pathway.

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HuR activates key oncogenic programs by regulating the Wnt/β-catenin pat...
(A) Compendium of normalized enrichment scores (NES) of target gene sets associated with the Wnt/β-catenin pathway after GSEA analysis of HuR-silenced ST88-14 MPNST cells (Supplemental Tables 5 and 6). Notably, there is general positive correlation in the activation of the pathways (highlighted in green) in shCtrl-infected cells. Circles denotes the number of enriched genes in each category, and colors represent FDR Q values. (B) GSEA plots showing enrichment of a MYC-induced target gene set in shCtrl cells, and a LEF1-repressed target gene set in shHuR#1-infected cells. (C) RIP-qPCR analysis showing binding of HuR to CTNNB1 and BCL9 in 4 MPNST cell lines (ST88-14, 90-8, S462, STS-26T). Data are normalized to control IgG IPs and are presented as mean ± SEM, 2-tailed unpaired Student’s t test. (D) Representative Western blots showing a general downregulation of Wnt/β-catenin pathway components, including key oncogenic downstream regulators, after HuR silencing in ST88-14 MPNST cells. Technical duplicates are shown, and similar results were obtained in 3 independent experiments. (E) Representative Western blots showing that lentivirus-based expression of constitutively active β-catenin 4A mutant (harbors alanine substitutions at S33, S37, T41, and S45, preventing its degradation) [pcw107-β-Cat (4A)] partially blocks the downregulation of the key downstream regulators c-MYC, SOX9, AURKA, and AURKB by HuR silencing (shH#3) in ST88-14 MPNST cells. Technical duplicates are shown, and similar results were obtained in 3 independent experiments. (F) Ectopic expression of constitutively active β-catenin 4A mutant partially blocks the effects of HuR silencing on cell numbers and ATP levels in ST88-14 MPNST cells. Data are normalized to shCtrl + pcw107-EV cells and are presented as mean ± SEM. Each data point represents 1 independent experiment; 1-way ANOVA with Tukey’s multiple-comparisons test. *P < 0.05; **P < 0.01; ****P < 0.001.