Analysis of hepatocarcinogenesis via the complex between the E3 ubiquitin ligase MDM2 and gankyrin

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Hepatocellular carcinoma is one of the most common cancers in Asia and Africa, where hepatitis virus infection and exposure to specific liver carcinogens are prevalent Gankyrin is overexpressed in most hepatocellular carcinomas. Gankyrin interacts with the S6 proteasomal ATPase and accelerates the degradation of the tumor suppressor pRb. Gankyrin is an anti-apoptofic oncoprotein and increases the degradation of another tumor suppressor p53. Gankyrin binds to Mdm2, an E3 ubiquitin ligase for p53, and potentiates the ubiquitylating activity. Thus, gankyrin is a cofactor that increases the activities of Mdm2 on p53 and probably targets polyubiquitylated p53 into the 26S proteasome. Gankyrin interacts with multiple proteins and forms the high-molecular-weight complex. In another complex, gankyrin binds to NF-kB and suppresses its activity at the transcriptional level by modulating acetylation via SIRT1, a class III histone deacetylase. Gankyrin plays an oncogenic role mainly at the early stages of human hepatocarcinogenesis, and IGFBP-5 inducible by gankyrin overexpression may be involved in it Gankyrin overexpression increases tumor growth, cell motility, invasiveness in vitro and tumor formation in vivo. Gankyrin overexpression is associated with poor prognosis in human esophageal squamous cell carcinoma.