HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis
Marta Palomo-Irigoyen, et al.
Marta Palomo-Irigoyen, et al.
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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 8

HuR regulates the RB/E2F pathway in MPNSTs.

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HuR regulates the RB/E2F pathway in MPNSTs. (A and B) GSEA plots showing...
(A and B) GSEA plots showing enrichment of functionally defined RB (A) and E2F1 (B) signature set in shCtrl-infected compared with shHuR#1-infected ST88-14 MPNST cells from Figure 6C. (C) Cartoon depicting regulatory components of the RB/E2F pathway in cell cycle regulation. By interacting with CDKs, cyclins form complexes (cyclin D with CDK4/6 and cyclin E with CDK2) that phosphorylate RB1 (phosphorylated RB1 is inactive). When RB1 is phosphorylated, E2F is released and can transcriptionally activate its target genes, enabling the G1/S transition of cell cycle. Cyclins can be regulated at the transcription level by the RAS-MEK-ERK pathway and at the translation level by mTOR via S6K and 4EBP1. p21 and p27 can bind to and inhibit cyclin-CDK complexes. (D) RIP-qPCR analysis showing binding of HuR to multiple genes in the RB/E2F pathway 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. (E) Representative Western blots showing a downregulation of several key RB/E2F pathway components after HuR silencing in ST88-14 MPNST cells, in general concordance with RIP-qPCR data. Technical duplicates are shown, and similar results were obtained in 3 independent experiments. *P < 0.05; **P < 0.01; ***P < 0.001.