Hepatitis B virus X protein induces the expression of MTA1 and HDAC1, which enhances hypoxia signaling in hepatocellular carcinoma cells

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-1a (HIF-1a) 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-1a, which was accompanied with dissociation of prolyl hydroxylases and von Hippel-Lindau tumor suppressor from HIF-1a. These results indicate that HBx-induced deacetylation is important for proteasomal degradation of HIF-1a. Further, we observed that protein levels of MTA1 and HDAC1 were increased in the liver of HBxtransgenic 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-1a, which may play a critical role in angiogenesis and metastasis of HBV-associated HCC.

Stimulation of Inducible Nitric Oxide by Hepatitis B Virus Transactivator Protein HBx Requires MTA1 Coregulator

“…MTA1 (metastatic tumor antigen 1), a component of nuclear remodeling histone deacetylate complex, is also modulated by HBx in liver cancer cells (26). MTA1 plays significant roles in both tumor biology and inflammation.…”

Metastasis-associated Protein 1/Histone Deacetylase 4-Nucleosome Remodeling and Deacetylase Complex Regulates Phosphatase and Tensin Homolog Gene Expression and Function

“…Our laboratory, along with others, has shown that MTA1 associates with class I HDACs-HDAC1 and HDAC2 (28,32,33). However, MTA1 association with class II HDACs has not, as of yet, been documented.…”

Liver X receptor mediates hepatitis B virus X protein–induced lipogenesis in hepatitis B virus–associated hepatocellular carcinoma #

“…Chang liver and Chang X-34, in which HBx gene expression is under the control of a doxycycline-inducible promoter, and SNU-354 were described previously. [22][23][24] HepG2 was obtained from the American Type Culture Collection. Cells were maintained in Dulbecco's modified Eagle's medium or Roswell Park Memorial Institute medium containing 10% fetal bovine serum at 37°C in a 5% CO 2 /95% air incubator.…”

“…Subcellular fractionation, western blotting, immunoprecipitation, and immunocytochemistry were basically performed as previously described with specific antibodies against LXR␣ (Affinity BioReagents, Golden, CO), LXR␣, LXR␤, HBx, SREBP-1c, PPAR␣, PPAR␤, PPAR␥, stearoyl-coenyzme A desaturase-1 (SCD-1), hemagglutinin, ␤-actin (Santa Cruz Biotech-nology, Santa Cruz, CA), carbohydrate-responsive element-binding protein (ChREBP; Novus Biologicals, Littleton, CO), FLAG (Sigma, St. Louis, MO), or ␣-tubulin (Calbiochem, San Diego, CA). [22][23][24][25] Antibodies against FAS were kindly provided by Dr. K.-S. Kim at Yonsei University College of Medicine.…”

“…The reporters LXRE-Luc, Gal4-tk-Luc, and SRE-Luc (where Gal4 is galactosidase 4, Luc is luciferase, and SRE is sterol regulatory element) and the expression vectors for LXR␣ and LXR␤ were as described previously. 22,23,25,26 The Myc-tagged HBx and FLAGtagged HBx were constructed by the insertion of HBx cDNA into pCMV-Myc (Clontech, Palo Alto, CA) and p3XFLAG 7.1 (Sigma), respectively. The pGAL4-LXR␣ was constructed by the insertion of the full-length coding region of human LXR␣ cDNA into the expression vector containing DNA binding domain (1-147 amino acids) of yeast GAL4.…”