1. ¹College of Pharmacy, Seoul National University, Seoul, Korea
2. ²Bio-MAX Institute, Seoul National University, Seoul, Korea
3. ³College of Veterinary Medicine, Seoul National University, Seoul, Korea
4. ⁴Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Correspondence: Dr M-O Lee, College of Pharmacy and Bio-MAX Institute, Seoul National University, San 56-1 Shillim-dong, Gwanak-gu, Seoul 151-742, Korea. E-mail: molee@snu.ac.kr

Received 11 October 2007; Accepted 6 November 2007; Published online 11 February 2008.

Abstract

Expression level of metastasis-associated protein 1 (MTA1) is closely related to tumor growth and metastasis in various cancers. Although increased expression level of MTA1 was observed in hepatocellular carcinoma (HCC), role of MTA1 complex containing histone deacetylase (HDAC) in hepatitis B virus (HBV)-associated hepatocarcinogenesis has not been studied. Here, we demonstrated that HBx strongly induced the expression of MTA1 and HDAC1 genes at transcription level. MTA1 and HDAC1/2 physically associated with hypoxia-inducible factor-1 (HIF-1) in vivo in the presence of HBx, which was abolished by knockdown of MTA1 by short interfering RNA (siRNA). HBx induced deacetylation of the oxygen-dependent degradation domain of HIF-1, which was accompanied with dissociation of prolyl hydroxylases and von Hippel–Lindau tumor suppressor from HIF-1. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBx-transgenic mice. Also, there was a higher expression of HDAC1 in HCC than in the adjacent non-tumorous cirrhotic nodules in 10 out of 12 human HBV-associated HCC specimens. Together, our data indicate a positive cross talk between HBx and the MTA1/HDAC complex in stabilizing HIF-1, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.