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.)

TRAIL-producing NK cells contribute to liver injury and related fibrogenesis in the context of GNMT deficiency

Glycine-N-methyltransferase (GNMT) is essential to preserve liver homeostasis. Thus, cirrhotic patients show low expression of GNMT that is absent in HCC samples. Accordingly, GNMT deficiency in mice leads to steatohepatitis, fibrosis, cirrhosis and HCC. Lack of GNMT triggers NK cell activation in GNMT(−/−) mice and depletion of TRAIL significantly attenuates acute liver injury and inflammation in these animals. Chronic inflammation leads to fibrogenesis, further contributing to the progression of chronic liver injury regardless of the etiology. Taking all this together, the aim of our study is to elucidate the implication of TRAIL-producing NK cells in the progression of chronic liver injury and fibrogenesis. For this we generated double TRAIL(−/−)/GNMT(−/−) mice where we found that TRAIL deficiency efficiently protected the liver against chronic liver injury and fibrogenesis in the context of GNMT deficiency. Next, to better delineate the implication of TRAIL-producing NK cells during fibrogenesis we performed bile duct ligation (BDL) to GNMT(−/−) and TRAIL(−/−)/GNMT(−/−) mice. In GNMT(−/−) mice, exacerbated fibrogenic response after BDL concurred with NK1.1(+) cell activation. Importantly, specific inhibition of TRAIL-producing NK cells efficiently protected GNMT(−/−) mice from BDL-induced liver injury and fibrogenesis. Finally, TRAIL(−/−)/GNMT(−/−) showed significantly less fibrosis after BDL than GNMT(−/−) mice further underlining the relevance of the TRAIL/DR5 axis in mediating liver injury and fibrogenesis in GNMT(−/−) mice. Finally, in vivo silencing of DR5 efficiently protected GNMT(−/−) mice from BDL-liver injury and fibrogenesis, overall underscoring the key role of the TRAIL/DR5 axis in promoting fibrogenesis in the context of absence of GNMT. CONCLUSION: Overall, our work demonstrates that TRAIL-producing NK cells actively contribute to liver injury and further fibrogenesis in the pathological context of GNMT deficiency, a molecular scenario characteristic of chronic human liver disease