Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation

Nieves Embade, David Fernández-Ramos, Marta Varela-Rey, Naiara Beraza, Marcella Sini, Virginia Gutiérrez de Juan, Ashwin Woodhoo, Nuria Martínez-López, Begoña Rodríguez-Iruretagoyena, Francisco Javier Bustamante, Ana Belén de la Hoz, Arkaitz Carracedo, Dimitris P. Xirodimas, Manuel S. Rodríguez, Shelly C. Lu, José M. Mato, María L. Martínez-Chantar

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63 Scopus citations

Abstract

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation, and survival, which are well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, which is in line with a role for HuR in tumorigenesis. However, the precise mechanism leading to changes in HuR expression remains unclear. In the liver, HuR plays a crucial role in hepatocyte proliferation, differentiation, and transformation. Here, we unraveled a novel mean of regulation of HuR expression in hepatocellular carcinoma (HCC) and colon cancer. HuR levels correlate with the abundance of the oncogene, murine double minute 2 (Mdm2), in human HCC and colon cancer metastases. HuR is stabilized by Mdm2-mediated NEDDylation in at least three lysine residues, ensuring its nuclear localization and protection from degradation. Conclusion: This novel Mdm2/NEDD8/HuR regulatory framework is essential for the malignant transformation of tumor cells, which, in turn, unveils a novel signaling paradigm that is pharmacologically amenable for cancer therapy.

Original languageEnglish (US)
Pages (from-to)1237-1248
Number of pages12
JournalHepatology
Volume55
Issue number4
DOIs
StatePublished - Apr 1 2012

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ASJC Scopus subject areas

  • Hepatology

Cite this

Embade, N., Fernández-Ramos, D., Varela-Rey, M., Beraza, N., Sini, M., de Juan, V. G., Woodhoo, A., Martínez-López, N., Rodríguez-Iruretagoyena, B., Bustamante, F. J., de la Hoz, A. B., Carracedo, A., Xirodimas, D. P., Rodríguez, M. S., Lu, S. C., Mato, J. M., & Martínez-Chantar, M. L. (2012). Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation. Hepatology, 55(4), 1237-1248. https://doi.org/10.1002/hep.24795