SIAH1 causes growth arrest and apoptosis in hepatoma cells through beta-catenin degradation-dependent and -independent mechanisms.
We have previously shown that expression of SIAH1 is frequently down-regulated in HCCs and associated with their advanced stages. It has been shown that SIAH1 functions in the phosphorylation-independent degradation of beta-catenin and induces apoptosis and growth arrest. To examine if the effects of SIAH1 overexpression depend on the altered beta-catenin signaling pathway, we transferred the SIAH1 gene into three hepatoma cell lines with different genetic backgrounds: HepG2 (mutant beta-catenin), SNU475 (mutant AXIN1), and Huh7 cells (wild type beta-catenin and AXIN1). SIAH1 significantly decreased aberrant beta-catenin signal in HepG2 and SNU475 cells and induced growth arrest and apoptosis. However, SIAH1 also induced apoptosis in Huh7 cells, which retained a normal membranous distribution pattern of beta-catenin. Immunoblotting study demonstrated that SIAH1 also reduces the amount of PEG10 protein, which is known to be frequently overexpressed in HCC and to promote cell proliferation. These data suggest that PEG10 is another target protein of SIAH1 to induce apoptosis in hepatoma cells. Our results should lead to a better understanding of the relationship between deregulation of beta-catenin signals and hepatocarcinogenesis. Further investigations into the mechanisms by which SIAH1 promotes apoptosis and suppresses cell growth should also allow for the discovery of new therapeutic strategies.
Yoshibayashi
Hiroshi
H
Department of Surgery, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan. hiro0221@kuhp.kyoto-u.ac.jp
Okabe
Hiroshi
H
Satoh
Seiji
S
Hida
Koya
K
Kawashima
Kazuhiko
K
Hamasu
Shinya
S
Nomura
Akinari
A
Hasegawa
Suguru
S
Ikai
Iwao
I
Sakai
Yoshiharu
Y
D017209:Apoptosis / Q000502:physiology*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000378:metabolism*; D009687:Nuclear Proteins / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
D009687:Nuclear Proteins; D051176:beta Catenin; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins