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

• Published in: Hepatology (Baltimore, Md.) Vol. 55; no. 4; pp. 1237 - 1248
• Main Authors: Embade, Nieves, Fernández-Ramos, David, Varela-Rey, Marta, Beraza, Naiara, Sini, Marcella, de Juan, Virginia Gutiérrez, Woodhoo, Ashwin, Martínez-López, Nuria, Rodríguez-Iruretagoyena, Begoña, Bustamante, Francisco Javier, de la Hoz, Ana Belén, Carracedo, Arkaitz, Xirodimas, Dimitris P., Rodríguez, Manuel S., Lu, Shelly C., Mato, José M., Martínez-Chantar, María L.
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.04.2012; Wiley; Wiley Subscription Services, Inc
• Subjects: Animals; Antigens; Biological and medical sciences; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; Case-Control Studies; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Transformation, Neoplastic - pathology; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Cytoplasm - metabolism; Disease Models, Animal; ELAV Proteins - metabolism; Gastroenterology. Liver. Pancreas. Abdomen; Hepatocytes - metabolism; Hepatocytes - pathology; Hepatology; Humans; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Mice; Mice, Inbred C57BL; NEDD8 Protein; Proto-Oncogene Proteins c-mdm2 - metabolism; Signal Transduction - physiology; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors; Ubiquitins - metabolism; Human; Stability; Rodentia; Hepatic disease; Malignant tumor; Colonic disease; Antigen; Liver cancer; Vertebrata; Regulation(control); Mammalia; Colon cancer; Mouse; Animal; Gastroenterology; Digestive diseases; Intestinal disease; Cancer
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.24795

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. (Hepatology 2012)