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 10

HuR regulates a core transcriptional circuitry in MPNST cells.

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HuR regulates a core transcriptional circuitry in MPNST cells. (A) GSEA ...
(A) GSEA plots showing enrichment of genes upregulated in MPNST cells by JQ1 treatment (fold change >1.5; adjusted P value < 0.05) (13) and shHuR#1-infected ST88-14 MPNST cells. (B) RIP-qPCR analysis showing binding of HuR to BRD2, BRD3, and BRD4 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. (C) Representative Western blots showing a downregulation of BRD proteins after HuR silencing in ST88-14 MPNST cells. (D) Violin plot showing the distributions of BRD2, BRD3, and BRD4 ChIP-Seq signal at enriched regions in shCtrl-infected and shHuR#1-infected ST88-14 MPNST cells. The y axis shows BRD ChIP-Seq signal in units of reads per million (rpm)/bp. The loss of BRD occupancy at BRD-enriched regions after HuR silencing is highly significant (BRD2, P = 4.44 × 10–16; BRD3, P = 1.332 × 10–15; BRD4, P = 1.332 × 10–15; Welch’s t test). (E) Gene regulatory networks among differentially expressed, epigenetically active TFs that are either direct or indirect targets of BRD proteins. Red and blue circles represent differentially upregulated and downregulated TFs, respectively, in shCtrl-infected cells. Light green edges indicate regulatory interactions unique to shCtrl cells, light blue edges indicate those unique to shHuR#1-infected cells, and black edges indicate those present in both phenotypes. Pointed arrows indicate activation, and blunted arrows indicate inhibition. Functional categories are based on Gene Ontology Biological Processes. (F) GSEA plot showing strong enrichment of epigenetically active TFs that are either direct or indirect targets of BRD proteins in shCtrl-infected compared with shHuR#1-infected ST88-14 MPNST cells. (G and H) ToppGene analysis of HuR-regulated TF network in MPNSTs (red circles from E), as classified according to pathway categories (G) or disease (H).