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

作者：Embade Nieves; Fernandez Ramos David; Varela Rey Marta; Beraza Naiara; Sini Marcella; Gutierrez de Juan Virginia; Woodhoo Ashwin; Martinez Lopez Nuria; Rodriguez Iruretagoyena Begona; Javier Bustamante Francisco; Belen de la Hoz Ana; Carracedo Arkaitz; Xirodimas Dimitris P; Rodriguez Manuel S; Lu Shelly C; Mato Jose M; Martinez Chantar Maria L^*

来源：Hepatology, 2012, 55(4): 1237-1248.

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)

• 出版日期2012-4