Article ; Online: HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis.
The Journal of clinical investigation
2020 Volume 130, Issue 7, Page(s) 3848–3864
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 ... ...
| 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. |
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| MeSH term(s) | Animals ; Carcinogenesis/genetics ; Carcinogenesis/metabolism ; Carcinogenesis/pathology ; Cell Line, Tumor ; Cell Proliferation ; ELAV-Like Protein 1/genetics ; ELAV-Like Protein 1/metabolism ; Humans ; Mice ; Neoplasm Metastasis ; Neoplasm Proteins/genetics ; Neoplasm Proteins/metabolism ; Nerve Sheath Neoplasms/genetics ; Nerve Sheath Neoplasms/metabolism ; Nerve Sheath Neoplasms/pathology ; Signal Transduction | |||||
| Chemical Substances | ELAV-Like Protein 1 ; ELAVL1 protein, human ; Neoplasm Proteins | |||||
| Language | English | |||||
| Publishing date | 2020-04-21 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 3067-3 | |||||
| ISSN | 1558-8238 ; 0021-9738 | |||||
| ISSN (online) | 1558-8238 | |||||
| ISSN | 0021-9738 | |||||
| DOI | 10.1172/JCI130379 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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