2012/01/31

New mechanism involved in the development of hepatocellular carcinoma and colon cancer.

Hepatocellular carcinoma (HCC) is a neoplasm with poor prognosis and represents the fifth most common cancer worldwide. The research team leaded by Dr. M. Luz Martínez-Chantar at the Metabolomics Unit of CICbioGUNE had previously reported that the RNA binding protein HuR plays and important role in liver proliferation and is tightly regulated during liver de-differentiation and differentiation. Increased levels of HuR are observed in surgically resected human HCC. Now this research group has discovered a new pathway that controls HuR expression due to stabilization through NEDDylation in human HCC and colon cancer. Needylation is a mechanism by which NEDD8 molecules conjugated to some proteins are able to induce their stabilization. Subsequent mutational analysis has led to identify the lysines residues required for HuR NEDDylation. The Martínez-Chantar's team have also demonstrated that the abundance of HuR in tumor cells is correlated with high levels of Mdm2 (an important protein that promotes needylation) through the action of MDM2 protein as an E3 NEDD8 ligase. These findings show for the first time that Mdm2-NEDD8 machinery and HuR are essential for the malignant transformation of cells, supporting the role of HuR in tumorigenesis and opening new strategies for therapeutic approaches. The manuscript describing these results (Embade N, Ferandez D et al, 2011) has been highlighted in the Section of Cancer in Nature Reviews of Gastroenterology and Hepatology.

References:

Mdm2 regulates HuR stability in human liver and colon cancer through neddylation.
Embade N, Fernández-Ramos D, Varela-Rey M, Beraza N, Sini M, de Juan VG, Woodhoo A, Martínez-López N, Rodríguez-Iruretagoyena B, Bustamante FJ, de la Hoz AB, Carracedo A, Xirodimas DP, Rodríguez MS, Lu SC, Mato JM, Martínez-Chantar ML. Hepatology. 2011 Nov 16. doi: 10.1002/hep.24795.

Mdm2-regulated stabilization of HuR by neddylation in HCC and colon cancer-a possible target for therapy.
McLarnon A. Nat Rev Gastroenterol Hepatol. 2011 Dec 13;9(1):4. doi: 10.1038/nrgastro.2011.241. No abstract available.
PMID: 22158377 [PubMed - in process]