Mdm2 regulates HuR stability in human liver and colon cancer through neddylation.

Hu antigen R (HuR) is a central RNA-binding protein regulating cell dedifferentiation, proliferation and survival, well-established hallmarks of cancer. HuR is frequently overexpressed in tumors correlating with tumor malignancy, 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 unravel a novel mean of regulation of HuR expression in HCC and colon cancer. HuR levels correlate with the abundance of the oncogene 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 malignant transformation of tumor cells, which in turn unveils a novel signaling paradigm, pharmacologically amenable for cancer therapy. (HEPATOLOGY 2011.)