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Murine double minute 2 regulates Hu antigen R stability in human liver and colon cancer through NEDDylation
Author(s) -
Embade Nieves,
FernándezRamos David,
VarelaRey Marta,
Beraza Naiara,
Sini Marcella,
de Juan Virginia Gutiérrez,
Woodhoo Ashwin,
MartínezLópez Nuria,
RodríguezIruretagoyena Begoña,
Bustamante Francisco Javier,
de la Hoz Ana Belén,
Carracedo Arkaitz,
Xirodimas Dimitris P.,
Rodríguez Manuel S.,
Lu Shelly C.,
Mato José M.,
MartínezChantar María L.
Publication year - 2012
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.24795
Subject(s) - neddylation , oncogene , cancer research , carcinogenesis , cancer , nedd8 , hepatocellular carcinoma , colorectal cancer , liver cancer , mdm2 , hepatology , biology , azoxymethane , malignant transformation , apoptosis , medicine , cell cycle , ubiquitin ligase , ubiquitin , biochemistry , gene
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. (H epatology 2012)