Hepatitis B virus X protein and the estrogen receptor variant lacking exon 5 inhibit estrogen receptor signaling in hepatoma cells.
Hepatitis B virus (HBV) X protein (HBx) is considered to play a role in the development of hepatocellular carcinoma (HCC) during HBV infection. HCC was shown to be more prevalent in men than in women. Estrogen, which exerts its biological function through estrogen receptor (ER), can inhibit HBV replication. ERDelta5, an ERalpha variant lacking exon 5, was found to be preferentially expressed in patients with HCC compared with patients with normal livers. Here, we report the biological role of ERDelta5 and a novel link between HBx and ERalpha signaling in hepatoma cells. ERDelta5 interacts with ERalpha in vitro and in vivo and functions as a dominant negative receptor. Both ERalpha and ERDelta5 associate with HBx. HBx decreases ERalpha-dependent transcriptional activity, and HBx and ERDelta5 have additive effect on suppression of ERalpha transactivation. The HBx deletion mutant that lacks the ERalpha-binding site abolishes the HBx repression of ERalpha. HBx, ERalpha and histone deacetylase 1 (HDAC1) form a ternary complex. Trichostatin A, a specific inhibitor of HDAC enzyme, can restore the transcriptional activity of ERalpha inhibited by HBx. Our data suggest that HBx and ERDelta5 may play a negative role in ERalpha signaling and that ERalpha agonists may be developed for HCC therapy.
Han
Juqiang
J
Beijing Institute of Biotechnology, 27 Tai-Ping Lu Road, Beijing 100850, People's Republic of China.
Ding
Lihua
L
Yuan
Bin
B
Yang
Xiao
X
Wang
Xiaohui
X
Li
Jiezhi
J
Lu
Qiujun
Q
Huang
Cuifen
C
Ye
Qinong
Q
D001665:Binding Sites; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D056284:Histone Deacetylase 1; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000821:virology*; D017434:Protein Structure, Tertiary; D012097:Repressor Proteins / Q000378:metabolism; D017384:Sequence Deletion; D015398:Signal Transduction; D015534:Trans-Activators / Q000737:chemistry / Q000378:metabolism*; D015533:Transcriptional Activation; D054334:Viral Regulatory and Accessory Proteins
D047628:Estrogen Receptor alpha; D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein; C110550:HDAC1 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases